JP2023506537A - Transmucosal therapeutic system containing agomelatine - Google Patents

Abstract

The present invention provides a transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layered structure comprising a therapeutically effective amount of agomelatine, e.g., an agomelatine transmucosal therapeutic system for use in a method of treatment, such agomelatine transmucosal The present invention relates to methods of treatment, including applying therapeutic systems, and processes for manufacturing such transmucosal therapeutic systems.
[Selection drawing] Fig. 2a

Description

The present invention relates to transmucosal therapeutic systems for transmucosal administration of agomelatine into the systemic circulation, as well as processes for making, methods of treatment, and uses thereof.

The active agent agomelatine (N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide) is a melatonergic antidepressant developed by Les Laboratoires Servier. The chemical structure is very similar to that of melatonin.

As a melatonergic agent that stimulates MT1 and MT2 receptors, agomelatine, like melatonin, can mediate synchronization of circadian rhythms. However, in addition to and in contrast to melatonin, agomelatine is also a 5-HT2B/5-HT2C antagonist, and blocking serotonergic 5HT2C receptors promotes the release of dopamine and norepinephrine in the prefrontal cortex. An unexpected synergistic effect has been observed for MT1/MT2 agonism and 5HT2C antagonism, and it is believed that this synergistic effect explains agomelatine's antidepressant action and unique clinical profile.

Agomelatine is approved in Europe under the trade names Valdoxan®, Melitor® and Thymanax® and is indicated for the treatment of Major Depressive Disorder (MDD). The currently available form is a film tablet containing a 25 mg dose, which is prescribed with an initial dose of 1 tablet taken at bedtime, with the option of doubling the dose if no improvement is seen. . Agomelatine is the only antidepressant on the market with the mechanism of action described above.

Oral agomelatine undergoes extensive first-pass and systemic metabolism, primarily via cytochrome CYP1A2. Agomelatine is well absorbed orally (>80%), but the overall bioavailability is very low (<5%), with significant inter-individual variability. The time to reach maximum plasma concentration as well as the elimination half-life t _1/2 are both about 1-2 hours, and at steady state the volume of distribution is 35 liters and the plasma protein binding is 95%.

Compared to other antidepressants, agomelatine appears to take effect more rapidly (usually within a week) and has some of the major side effects commonly known with other antidepressants, such as weight gain. , sexual dysfunction, anticholinergic symptoms and cardiotoxicity appear to be reduced. However, agomelatine carries a risk of hepatotoxicity, the mechanism of which remains unclear, manifested as increased alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) levels, with some exceptional In cases, outcome was fatal or required liver transplantation. In addition, hepatic impairment has also been reported to be associated with significantly increased agomelatine exposure, with up to 140-fold higher AUC and c in patients with moderate hepatic impairment compared to healthy subjects. _{A max} value was observed.

Servier and Novartis endeavored to establish a sublingual dosage form of agomelatine, presumably to avoid first-pass metabolism and its associated drawbacks outlined above (low oral bioavailability and hepatotoxicity); Placebo-controlled randomized trials were conducted with 1 and 2 mg (Servier) or 0.5 and 1 mg of agomelatine sublingual tablets (Novartis). There are no published results for the 2008/2009 Servier trial. The Novartis study, which began in 2011/2011, showed that sublingual agomelatine was no more effective than placebo, or at least less liver toxic, but had no clear dose-response relationship. On the point, it was essentially a failure. It appears that one of the reasons for the failure of the trial was the pronounced irritant sensation caused by agomelatine when administered to the oral mucosa. As a result, the FDA has decided not to approve this drug in the United States, even though it is superior to other active agents in treating MDD.

Several patent applications from Servier indicate that the first approach to provide novel dosage forms, e.g. tablets, also referred to as "orodispersible" formulations, was to rapidly replenish in minutes, such as less than 3 minutes or even less than 1 minute. , presumably to obtain a very fast onset of release, avoiding the associated penalties of enteral delivery and hepatic first-pass effect as much as possible. It's for. A more recent approach is to use inhaled Agomelatine, which aims to dissolve or disintegrate more slowly in the mouth to keep oral agomelatine concentrations low enough to limit the stinging sensation. included buccal formulations such as tablets with However, this carries the risk that the tablet will be swallowed prematurely by the patient, ie before all the active substance has been released. The bulk of the active substance is then released after some time, leaving only placebo cores without active substance to ensure that active substance release is nearly complete even if the patient swallows prematurely. proposed bi- or multi-layer tablets containing, for example, a placebo core.

Nevertheless, these orodispersible formulations do not seem to completely solve the problem of patient compliance that may be induced by agomelatine, which causes irritative sensations, and premature tablet release. Swallowing is not prevented, only its effect is mitigated. Incomplete active release is still a risk depending on the timing of unintentional swallowing of the tablet. In addition, sucking the tablet for an extended period of time means that the patient must hold disturbing objects in the oral cavity, which is disadvantageous with respect to patient compliance. Finally, the drug delivery mechanism of such orodispersible formulations depends on the active substance first dissolving in saliva (open system), which is why control of drug concentration and consequently drug delivery is very difficult. . For all these reasons, there may currently be no Agomelatine formulations on the market other than the conventional oral tablets outlined above.

Transmucosal therapeutic systems, or transmucosal delivery systems (sometimes also called buccal patches), consist of one or more thin layers that are applied to the oral mucosa and adhere to deliver drugs over a period of time. deliver. Dosage forms in the form of thin films for application in the oral cavity are sometimes referred to as "oral thin films" or OTFs, although OTFs are not necessarily intended to adhere to mucous membranes. In a transmucosal therapeutic system, the active agent is contained in a dissolvable layer and the film adheres to the mucosa, so active agent delivery can be achieved by direct active agent release from the transmucosal therapeutic system to the mucosa, as well as the oral cavity as outlined above. This is achieved in combination with indirect active agent delivery via dissolution in saliva, such as an intradispersible formulation. To prevent the indirect active agent delivery inherent in open systems, a backing layer may be employed, which serves to protect the active agent-containing layer from the rest of the oral cavity, particularly environmental saliva. . In either case, OTF is not a disturbing object in the mouth because the film attached to the mucosa does not move freely in the oral cavity, and because the film is usually thin enough to be imperceptible to the patient once applied. It is advantageous compared to orodispersible formulations that are intended to be inhaled in that they do not cause the negative sensation of being there.

However, transmucosal therapeutic systems are a relatively new form of drug delivery, implying limited knowledge of formulation technology. Formulating a suitable dosage form for transmucosal delivery by OTF is difficult due to many aspects to be considered and issues to be resolved. The main requirements for such transmucosal therapeutic systems are good adhesion and penetration of the active substance combined with appropriate behavior and disintegration time. Tactile sensations, ie, good feel in the mouth, as well as film stability (ie, low friability) prior to application are also important. Agomelatine's low solubility makes formulation of the material difficult and, as outlined above, a key issue is to address the pungent sensations the active material causes in the oral cavity. In addition, since agomelatine is primarily used to resynchronize circadian rhythms, the desired drug release profile is a rapid initial increase in drug delivery followed by an overnight only, preferably tapering release.

To date, there is no commercially available agomelatine transmucosal therapeutic system, and applicants are unaware of any research or investigation regarding such an agomelatine transmucosal therapeutic system.

In summary, there is a great need for an alternative administration of agomelatine that overcomes the shortcomings of oral as well as sublingual routes of administration. As outlined above, a transmucosal therapeutic system could address these disadvantages.

Therefore, there is a need in the art for an agomelatine transmucosal therapeutic system.

It is an object of the present invention to provide an agomelatine transmucosal therapeutic system as an alternative administration of agomelatine that overcomes the above-mentioned drawbacks of current agomelatine administrations.

It is therefore an object of the present invention to provide an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine that provides a particularly high permeation rate, thus sufficient to achieve a therapeutically effective dose.

A further object of the present invention is an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine that provides a drug release profile with a rapid initial increase, allowing for an overnight application suitable for administration, e.g., just before bedtime. to provide.

It is also a further object of the present invention to provide an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine that does not cause irritation to the mucous membranes or otherwise in the oral cavity.

Another object of the present invention is to provide an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine, eg, that provides adequate adherence to the mucosa, not only initially, but over time.

A further object of the present invention is to provide suitable disintegration, for example, not only with respect to disintegration time, but also with respect to the integrity of the transmucosal treatment system (when multiple layers are present, the layers do not come apart prematurely). To provide an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine that provides behavior.

Another object of the present invention is to provide an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine that has reduced hepatotoxicity and inter-individual variability and increased bioavailability when compared to oral administration. .

It is also an object of the present invention to provide an agomelatine transmucosal therapeutic system for transmucosal administration of agomelatine that provides good tactile sensation, ie, good feel in the mouth.

A further object of the present invention is a transmucosal formulation of agomelatine that provides good patient compliance and/or is simple and cost-effective to manufacture, according to the need for convenient application and handling in terms of size and thickness. To provide an agomelatine transmucosal therapeutic system for administration.

These and other objects are achieved by the present invention, according to one aspect relating to a transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layered structure, said mucoadhesive layered structure comprising:
A) a backing layer; and B)
i) agomelatine; and ii) an agomelatine-containing layer comprising a first soluble film former.

According to one particular embodiment of the invention, the transmucosal therapeutic system according to the invention is for use in a method of treatment, preferably for treating major depression.

According to another embodiment, the present invention relates to a method of treatment, particularly a method of treating major depression, comprising applying a transmucosal therapeutic system according to the present invention to a mucosal membrane of a human patient.

According to yet another embodiment, the present invention relates to the use of the transmucosal therapeutic system of the present invention for the manufacture of a medicament for treatment, preferably for treating major depression.

According to yet another particular aspect, the present invention relates to a process for manufacturing an agomelatine-containing layer, the process comprising:
i) combining at least agomelatine and a first soluble film former in a solvent to obtain a first coating composition;
ii) coating a first coating composition onto a release liner; and iii) drying the first coated coating composition to form an agomelatine-containing layer.

According to a particular embodiment, the invention also relates to a transmucosal therapeutic system for transmucosal administration of agomelatine obtainable by such manufacturing process.

According to certain embodiments, the present invention also relates to a transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least A) a backing layer; and B)
i) 3-7% by weight agomelatine;
ii) a first soluble film former, and iii) 5-15% by weight fatty acid;
iv) 0.1-2.0% by weight of one or more sweeteners, and v) 0.2-2.0% by weight of a flavoring agent, comprising an agomelatine-containing layer;
the first soluble polymer is hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose;
The areal weight of the agomelatine-containing layer is in the range of 100 to 150 g/m ² ,
The backing layer comprises 5-15% by weight fatty acid, 0.1-2.0% by weight of one or more sweeteners, 0.2-2.0% by weight flavoring agent, and a second dissolvable film. a forming agent, the second soluble film forming agent being a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose;
The areal weight of the backing layer ranges from 100 to 300 g/m ² .

Within the meaning of the present invention, the term "transmucosal therapeutic system" or "transmucosal delivery system" means that the active agent (agomelatine) is administered into the systemic circulation via transmucosal delivery by application to the oral mucosa. A discrete dosage system applied to a patient's mucosa and comprising a therapeutically effective amount of agomelatine in a mucoadhesive lamina, optionally comprising an additional overlay on top of the agomelatine-containing mucoadhesive lamina refers to the entire unit. The mucoadhesive layer structure may be placed on a release liner (removable protective layer) and thus the transmucosal therapeutic system may further include a release liner. Within the meaning of the present invention, the term "transmucosal therapeutic system" specifically refers to a system that provides passive transmucosal delivery, excluding active agent transport similar to methods involving microporation. Also, in contrast to certain oral thin films (sometimes called "flash wafers") which are not necessarily mucoadhesive and are intended to disintegrate very quickly in saliva, enteral delivery is Totally not intended for mucosal treatment systems.

Within the meaning of the present invention, the term "a mucoadhesive layer structure containing agomelatine" or "a mucoadhesive layer structure containing a therapeutically effective amount of agomelatine" refers to an active agent that provides a release area for agomelatine during administration. Refers to the containing structure. Any additional overlays increase the overall size of the transmucosal therapeutic system, but not the release area. The agomelatine-containing mucoadhesive layer structure comprises at least one agomelatine-containing layer.

Within the meaning of the present invention, the term "therapeutically effective amount" means a blood level similar to that obtained with a single dose of 25 mg oral agomelatine when administered to a patient by a transmucosal therapeutic system. Refers to the amount of active agent in the transmucosal therapeutic system sufficient to provide agomelatine blood levels in the range (eg, from about 10% to about 1000%, measured as AUC).

Within the meaning of the present invention, terms such as "active substance" and "active agent" and the term "agomelatine" refer to any pharmaceutically acceptable chemical and morphological form and physical state. It refers to agomelatine. These forms include, but are not limited to, agomelatine in its free, dissociated or any associated form, such as hydrates, solvates, etc., as well as micronized forms, crystalline forms, and especially one of its polymorphic forms. and/or in particulate form, which may be in amorphous form, as well as any hybrid forms of agomelatine or mixtures thereof of any of the foregoing forms. Agomelatine may be dissolved or dispersed, or partially dissolved and partially dispersed, when contained in a medium such as a solvent.

When agomelatine is referred to as being used in a particular form in the manufacture of a transmucosal therapeutic system, this does not exclude interactions between this form of agomelatine and other components of the agomelatine-containing self-adhesive layered structure. As such, the active agent is present in another form in the final transmucosal therapeutic system. This means that even though agomelatine is contained in free, dissociated form, it may be present in the final transmucosal therapeutic system in the form of a hydrate or solvate, or in one of its polymorphic forms. It means that it can be present in the final transmucosal therapeutic system in an amorphous form. Unless otherwise indicated, the amount of agomelatine specifically in the mucoadhesive layer structure relates to the amount of agomelatine included in the transmucosal therapeutic system during manufacture of the transmucosal therapeutic system and is calculated on the basis of agomelatine in free form. i.e. if agomelatine is included in an amount of 0.1 mmol, the amount of agomelatine in the self-adhering layer structure is taken as 24.3 mg within the meaning of the invention (the molecular weight of agomelatine is 243 g/mol ), regardless of whether agomelatine was included in the transmucosal therapeutic system during manufacture in its free form or in any associated form.

The agomelatine starting material included in the transmucosal therapeutic system during manufacture of the transmucosal therapeutic system can be in the form of particles. Agomelatine may be present in the mucoadhesive layer structure in the form of particles, for example dispersed and/or dissolved.

Within the meaning of the present invention, the term "particle" refers to a solid particulate material comprising individual particles, the dimensions of which are insignificant compared to the material. In particular, particles are solids, including plastics/deformable solids, including amorphous and crystalline materials.

Within the meaning of the present invention, the term "disperse" refers to a step or combination of steps in which the starting material (eg agomelatine) is not completely dissolved. Dispersion in the sense of the present invention comprises partial dissolution of the starting material (eg the agomelatine particles) depending on the solubility of the starting material (eg the solubility of agomelatine in the coating composition).

There are two main types of transmucosal therapeutic systems: those that use a backing layer and those that do not. As outlined in the introductory background section, active agent delivery in open transmucosal therapeutic systems without a backing layer has always been direct delivery from the transmucosal therapeutic system through the mucosa at the site of attachment, and transmucosal delivery. There will be a combination of indirect delivery via dissolution of the active agent from the mucosal therapeutic system to the saliva and from the saliva through the mucosa. The proportion of different delivery routes depends primarily on factors such as the solubility of the active agent and the disintegration time of the transmucosal therapeutic system. The higher the solubility and the faster the disintegration of the transmucosal therapeutic system, the more likely dissolution in saliva will be favored over direct delivery to the mucosa at the site of attachment. Such indirect delivery has the advantage of providing a practical increase in mucosal surface area from which the active agent is systemically released. However, dissolution in saliva means that it is difficult to control the concentration of the active substance and hence the final delivered amount, and the risk of enteral delivery through unintentional swallowing of saliva is serious. Especially with agomelatine, it also has the problem that the active substance, which has been proven to provide potentially stimulating sensations, dissolves freely throughout the oral cavity.

A transmucosal therapeutic system using a backing layer has an entirely different approach. In such systems, the use of a backing layer substantially limits the delivery route to direct transmucosal delivery, which is much better controlled and reduces the risk of enteral delivery, and most advantageously, agomelatine. It is believed that by limiting the salivary dissolution of , the pungent sensation caused by this active can be substantially reduced. A challenge for transmucosal therapeutic systems using backing layers is nonetheless to provide adequate transmucosal penetration and delivery of the active agent. Thus, in the sense of the present invention, a "backing layer" within a transmucosal therapeutic system is capable of preventing dissolution in saliva of (at least a substantial amount of) an active substance contained within the transmucosal therapeutic system. Any layer. Such backing layers can be non-dissolving or dissolvable over time. In the latter case, the time it takes for the backing layer to dissolve is at least as long as the time it takes for the (substantial amount) of the active agent to be delivered across the mucosa.

In this context, "dissolve", "dissolvable" with respect to any of the layers of the transmucosal therapeutic system (e.g., backing layer, active agent-containing layer) and with respect to film formers when cast into a film. , "dissolve" and the like are to be understood very broadly and do not have a strict chemical meaning of chemically dissolving a molecule in a solvent. The "dissolved" material is free to move around in a liquid (e.g. saliva), so that what lies beneath the layer (i.e. the mucous membrane if the mucosal contact layer is dissolved, or e.g. the active substance-containing If the backing layer is dissolved prior to the layer, the conversion of the solid state to the liquid state of the layer, e.g. Liquid formation, gelation of films and disintegration of gels into smaller pieces, etc., must all be considered "dissolution" within the meaning of the present invention. In preferred embodiments, the meaning is limited to the normal chemical meaning of dissolving the molecule in a solvent. It should be noted that the term "dissolve" with respect to the substance itself, such as the active agent agomelatine, or any excipients, continues to be used in its normal chemical sense of dissolving the molecule in a solvent. For example, the dissolved form of agomelatine clearly does not include the dispersed form of agomelatine. The film-forming agent itself should be present in the coating composition in a dissolved form (e.g., non-dispersed, small-part gel form, etc.) in the common chemical sense during manufacture of the transmucosal therapeutic system. However, when a film former is cast into a film, "dissolving" such a film also includes gelation of the film and the disintegration of smaller portions of the gel into a gel.

The active agent-containing layer is, for example, the final, solidified layer obtained after coating and drying the solvent-containing coating composition. The active agent-containing layer can also be produced by laminating two or more such solidified layers (eg, dry layers) of the same composition to provide the desired areal weight. The active agent-containing layer may be mucoadhesive (in the form of a mucoadhesive layer), or the transmucosal therapeutic system may include an additional mucoadhesive mucosal contact layer to provide sufficient adhesion. . In particular, the active agent-containing layer is a mucoadhesive layer.

Within the meaning of the present invention, the term "mucoadhesive" is used in particular to adhere to and on contact with mucous membranes, but when dry, preferably non-adhesive, e.g. refers to a material that can be manipulated for application to the oral cavity without unintentionally adhering to the skin of, for example, a finger. A mucoadhesive layer is "self-adhesive" when in contact with a mucosa, ie, typically provides adhesion to the mucosa such that no further assistance is required for fixation. The adhesion strength is preferably so strong that typical movements in the oral cavity are not sufficient to displace the mucoadhesive layer attached to the mucosa. A "mucoadhesive" layered structure includes a mucoadhesive layer for mucosal contact which may be provided in the form of a mucoadhesive active agent-containing layer or in the form of an additional layer, ie, a mucoadhesive mucocontact layer. A mucoadhesive overlay may further be employed to improve adhesion.

Within the meaning of the present invention, the term "mucosal contact layer" refers to the layer included in the transmucosal therapeutic system that is in direct contact with the patient's mucosa during administration. When the transmucosal therapeutic system includes a mucosal contact layer, the other layers do not contact the mucosa and do not necessarily have mucoadhesive properties. The release area is provided by the area of the active agent-containing layer. A mucosal contact layer may be used to enhance adhesion. The size of the additional mucosal contact layer and the active agent-containing layer is usually coextensive and corresponds to the release area.

Within the meaning of the present invention, the term "areal weight" refers to the dry weight of a particular layer, eg the active agent-containing layer, provided in g/ ^m2 . Areal weight values are subject to a tolerance of ±10%, preferably ±7.5% due to manufacturing variations.

Unless otherwise indicated, "%" refers to weight percent.

Within the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, homopolymers consisting of one type of monomer and two Includes copolymers of more than one type of monomer. The polymer may be of any structure, such as linear, star, comb, brush, etc., and in the case of copolymers, of any monomer sequence, e.g., alternating, statistical, block copolymers, or graft polymers. can be Minimum molecular weights vary depending on the type of polymer and are known to those skilled in the art. The polymer may, for example, have a molecular weight greater than 2,000 Daltons, preferably greater than 5,000 Daltons, more preferably greater than 10,000 Daltons. Correspondingly, compounds with molecular weights less than 2,000 Daltons, preferably less than 5,000 Daltons, or more preferably less than 10,000 Daltons are commonly referred to as oligomers.

Within the meaning of the present invention, the term "crosslinker" refers to a substance capable of cross-linking the functional groups contained within the polymer.

Within the meaning of the present invention, the term "mucoadhesive overlay" is located on top of an agomelatine-containing mucoadhesive layer structure, does not contain an active agent, has a larger area than an active agent-containing structure, and is viscous to the mucosa. Refers to a mucoadhesive layer that provides additional surface area for adhesion, but not active agent release area. The overall adhesive properties of the transmucosal therapeutic system are thereby enhanced.

A transmucosal therapeutic system according to the present invention can be characterized by certain parameters measured in an in vitro permeation test.

In vitro permeation studies are performed using human or animal mucosa, preferably skinned split-thickness porcine mucosa with a thickness of 400 μm and intact barrier function, in phosphate buffer pH 5.5 or 7.4. as the receiving medium (37° C.), such that the receiving medium may contain, for example, 60% by volume phosphate buffer (pH 5.5), 30% by volume dipropylene glycol and 10% by volume acetonitrile, Up to 40% by volume of organic solvents such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG400 are added or not.

Unless otherwise indicated, in vitro permeation studies were performed using skinned split-thickness porcine mucosa (esophageal mucosa) with a thickness of 400 μm and intact barrier function, phosphate buffer pH 7.4 in a receptive medium (37 °C). The amount of active substance permeated into the receiving medium is determined at regular intervals using an HPLC method with a UV photometric detector by taking a sample volume. The measured amount of active permeated relates to the amount permeated between the last two sampling time points and not to the total amount permeated so far.

Therefore, within the meaning of the present invention, the parameter "permeation dose" is given in μg/cm ² and is the amount of active substance permeated in the sample interval at a certain elapsed time per area of release. Related. For example, in an in vitro permeation test as described above in which the amount of active substance permeated into the receiving medium was measured, for example, at 0, 2, 4, 8, 12, and 24 hours, the "permeation amount" of the active substance was , for example, over a sample interval of 8 hours to 12 hours, corresponding to the measurement results at the 12 hour time point.

Permeation can also be provided as "cumulative permeation" which corresponds to the cumulative amount of active permeated at a particular point in time. For example, in an in vitro permeation test as described above in which the amount of active substance permeated into the receiving medium was measured, for example, at 0, 2, 4, 8, 12, and 24 hours, the amount of active substance at 12 hours was "Cumulative amount permeated" corresponds to the total permeation amount from 0 to 2 hours, from 2 to 4 hours, from 4 to 8 hours, and from 8 to 12 hours.

Within the meaning of the present invention, the parameter "mucosal permeation rate" ^for a particular sample interval at a particular elapsed time is provided in units of μg/(cm ² h) and Calculated by dividing the amount of permeation at said sample interval, as measured by the in vitro permeation test as per , by the time at said sample interval. For example, the amount of active substance permeated into the receiving medium was determined, for example, at 0, 2, 4, 8, 12, and 24 hours. The "mucosal permeation rate" is calculated as the amount permeated in the sample interval from 8 hours to 12 hours divided by 4 hours.

A "cumulative mucosal permeation rate" can be calculated from each cumulative permeation rate by dividing the cumulative permeation rate by the elapsed time. For example, in an in vitro permeation test as described above in which the amount of active substance permeated into the receiving medium was measured at, for example, 0, 2, 4, 8, 12, and 24 hours, the "cumulative mucosal permeation Velocity' is calculated as the cumulative permeation at 12 hours (see above) divided by 12 hours.

Within the meaning of the present invention, the above parameters permeation dose and mucosal permeation rate (and cumulative permeation dose and cumulative mucosal permeation rate) refer to mean values calculated from three in vitro permeation test experiments.

Transmucosal therapeutic systems according to the present invention can also be characterized by certain parameters measured in in vivo clinical studies.

Within the meaning of the present invention, the term "administration" refers to the application of the dosage form, i.e. the transmucosal therapeutic system, to the oral mucosa of a patient, after which it remains on the mucosa until the agomelatine-containing layered structure dissolves. be.

In typical continuous treatment for MDD, the frequency of drug administration is kept high enough to maintain therapeutically effective plasma concentrations. The interval between two dosage form administrations, also called dosing interval, should be adjusted accordingly. Within the meaning of the present invention, the term "dosage interval" refers to the period between two consecutive administrations, i.e. the interval between two consecutive time points at which the transmucosal therapeutic system is applied to the patient's oral mucosa. Point. In order to consistently maintain plasma concentrations at therapeutic levels, the transmucosal therapeutic system must be replaced as soon as or shortly after the active agent-containing layer of the previous transmucosal therapeutic system has dissolved, at which point a new A therapeutic system is applied. In such a mode (constant plasma levels for 24 hours), the dosing interval corresponds approximately to the disintegration time of the active agent-containing layer and can be, for example, 6 hours, 8 hours or 12 hours. After this period of time, the active agent-containing layer of the transmucosal therapeutic system dissolves, any residue (eg, non-dissolving backing layer) is removed from the oral cavity, and a new transmucosal therapeutic system is applied. Thus, a 12-hour dosing interval allows for a twice-daily transmucosal treatment system exchange regimen with 24-hour treatment.

However, for continued treatment with agomelatine, the transmucosal therapeutic system is usually administered once daily (24 hour dosing interval), preferably at bedtime, and the disintegration time is preferably shorter than the dosing interval. right. The transmucosal therapeutic system may be applied to the patient's mucosa shortly (eg, 5-30 minutes) before bedtime, particularly to allow for delayed onset of drug action. In the case of agomelatine, 24-hour maintenance of plasma concentrations at therapeutic levels does not appear to be necessary, or may even be contraindicated for resynchronization of circadian rhythms, so the inclusion of active agents in previous transmucosal therapeutic systems There is no need to apply another transmucosal treatment system as soon as the layer dissolves, eg, the next morning, so the patient need not apply a transmucosal treatment system thereafter, eg, throughout the day.

Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory where the experiment is performed, usually in the range 15-35°C, preferably about 18-25°C. is within.

Within the meaning of the present invention, the term "patient" refers to a subject who has exhibited clinical signs of a particular condition or symptoms suggesting the need for treatment, treated preventively or prophylactically against a condition. refers to a subject who is diagnosed with, or who has been diagnosed with, a condition to be treated.

Within the meaning of the present invention, the term "pharmacokinetic parameter" refers to plasma curves obtained in clinical studies, e.g. by single or multiple administrations of the agomelatine transmucosal therapeutic system to healthy human subjects, e.g. , C _max , C _t and AUC _t1-t2 . Pharmacokinetic parameters for individual subjects are expressed as arithmetic and geometric means, e.g., mean C _max , mean AUC _t , and mean AUC _INF , and additional statistics, e.g., standard deviation and standard error of each, minimum, maximum , and the mean (median) if the list of values is ranked. In the context of the present invention, pharmacokinetic parameters such as C _max , C _t and AUC _t1-t2 refer to arithmetic or geometric mean values, preferably to geometric mean values. It cannot be ruled out that the absolute mean values obtained for a particular transmucosal therapeutic system in clinical studies vary to some extent from study to study. A reference formulation, eg any product according to the invention in the future, can be used as an internal standard to allow comparison of absolute mean values between studies. A comparison of the AUC per release area for each reference product in the previous and subsequent studies can be used to derive a correction factor to account for study-to-study differences.

Clinical studies according to the present invention refer to studies conducted in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.

Within the meaning of the present invention, the term "healthy human subject" has a body weight in the range of 55 kg to 100 kg and a body mass index (BMI) in the range of 18 to 29, as well as normal physiological parameters such as blood pressure. Refers to male or female subjects. Healthy human subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria based on and in accordance with ICH recommendations.

Within the meaning of the present invention, the term "subject population" refers to at least 10 individual healthy human subjects.

Within the meaning of the present invention, the term "geometric mean" refers to the mean of log-transformed data transformed back to the original scale.

Within the meaning of the present invention, the term "arithmetic mean" refers to the sum of all observations divided by the total number of observations.

Within the meaning of the present invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the total amount of active agent absorbed into the blood circulation and is therefore a measure of bioavailability.

Within the meaning of the present invention, the parameter “AUC _t1-t2 ” is provided in units of (ng/mL) h and relates to the area under the plasma concentration-time curve from time t1 to time t2, linear trapezoidal Calculated by law.

Within the meaning of the present invention, the parameter “C _max ” is provided in units of (ng/mL) and relates to the maximum observed plasma concentration of the active agent.

Within the meaning of the present invention, the parameter “C _t ” is provided in (ng/mL) and relates to the plasma concentration of active agent observed at time t.

Within the meaning of the invention, the parameter “t _max ” is provided in hours and relates to the time when the C _max value is reached. In other words, t _max is the time point of maximum observed plasma concentration.

Within the meaning of the present invention, the parameter “t _lag ” is provided in hours and is the administration time (in the case of a transmucosal therapeutic system, the time at which the transmucosal therapeutic system is first applied to the oral mucosa, i.e. , t=0) and the time of appearance of measurable plasma concentrations. The t _lag can be approximated, or represented by the median value, as the mean arithmetic value of the first time points at which measurable (ie, non-zero) active agent plasma concentrations are obtained.

Within the meaning of the present invention, the term "mean plasma concentration" is provided in units of (ng/mL) and is the mean of the individual plasma concentrations of the active agent, eg agomelatine, at each time point.

Within the meaning of the present invention, the term "coating composition" refers to any drug-in-solvent layer that can be coated onto a backing layer or release liner to form an active agent-containing layer when dried. It refers to a composition that includes ingredients.

Within the meaning of the present invention, the term "dissolving" in the context of coating composition preparation, e.g. refers to the process of obtaining a solution that does not contain any particles at

Within the meaning of the present invention, the term "solvent" preferably refers to volatile organic liquids such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, heptane, toluene and their It refers to any liquid substance that is a mixture.

Within the meaning of the present invention, unless otherwise specified, the term "about" refers to an amount ±10% of the amount disclosed. In some embodiments, the term "about" refers to an amount ±5% of the amount disclosed. In some embodiments, the term "about" refers to an amount ±2% of the amount disclosed.

Figure 2 shows Agomelatine mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 1a-1f for 0-7 hour time points. Figure 2 shows agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 1a-1f after 7 hours. Figure 2 shows the agomelatine mucosal permeation rate of transmucosal therapeutic systems prepared according to Examples 1a, 2 and 3a for time points 0-7 hours. Figure 2 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 1a, 2 and 3a after 7 hours. Figure 2 shows the agomelatine mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 3a-3d for 0-6 hour time points. Figure 2 shows the agomelatine mucosal permeation rate of transmucosal therapeutic systems prepared according to Examples 3b and 3e-3h for time points 0-6 hours. Figure 2 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 3a-3h after 6 hours. Figure 2 shows the agomelatine mucosal permeation rate of transmucosal therapeutic systems prepared according to Examples 4a-4f for 0-6 hour time points. Figure 4 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 4a-4f after 6 hours. Figure 2 shows the agomelatine mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 4b and 5a-5d for 0-6 hour time points. Figure 2 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 4b and 5a-5d after 6 hours. Figure 2 shows Agomelatine mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 6a-6d for 0-6 hour time points. Figure 10 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 6a-6d after 6 hours. Figure 10 shows the agomelatine mucosal permeation rate of transmucosal therapeutic systems prepared according to Examples 4b, 6b, 6c, 6d, 7e and 7g for 0-4 hour time points. Agomelatine mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 4b, 7a-7d and 7f for 0-4 hour time points. Figure 2 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 4b, 6b, 6c, 6d and 7a-7g after 7 hours. Figure 2 shows agomelatine plasma concentrations obtained in an in vivo clinical study of transmucosal therapeutic systems prepared according to Examples 8a-8c for 0-8 hour time points. Figure 2 shows the agomelatine mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 4b and 9a-9f for 0-4 hour time points. Figure 10 shows Agomelatine utilization of transmucosal therapeutic systems prepared according to Examples 4b and 9a-9f after 4 hours. Figure 10 shows the total potential degradants and amount of agomelatine detected in storage stability tests at different time points, 25°C and 60% RH and 40°C and 75% RH, for TTS prepared according to Example 9a. Figure 10 shows the total potential degradants and amount of agomelatine detected in storage stability tests at different time points, 25°C and 60% RH and 40°C and 75% RH, for TTS prepared according to Example 9c.

Structures of Transmucosal Therapeutic Systems The present invention relates to transmucosal therapeutic systems for transmucosal administration of agomelatine comprising a mucoadhesive layered structure containing agomelatine.

The mucoadhesive layer construction contains a therapeutically effective amount of agomelatine and comprises a backing layer and an agomelatine-containing layer comprising i) agomelatine and ii) a first dissolvable film former.

Thus, a transmucosal therapeutic system for transmucosal administration of agomelatine comprises a mucoadhesive layered structure containing a therapeutically effective amount of agomelatine, said mucoadhesive layered structure comprising:
A) a backing layer; and B)
i) agomelatine; and ii) an agomelatine-containing layer comprising a first soluble film former.

The transmucosal therapeutic system of the present invention specifically attempts to address patient compliance issues and potential risks of hepatotoxicity by employing a backing layer. It is believed that the backing layer protects the active agent from dissolution in saliva and thus may prevent unintended delivery via the gastrointestinal route as well as the irritant sensation that the active agent agomelatine causes on mucous membranes.

As outlined above, a backing layer in the sense of the present invention is a transmucosal therapeutic system capable of preventing dissolution in saliva of (at least a substantial amount of) an active substance contained within the transmucosal therapeutic system. is any layer within Further details regarding the backing layer will be discussed in a separate section below.

In some particular embodiments, the mucoadhesive layer structure comprises
It may further comprise one or more additional layers selected from C) a mucosal contact layer, and D) a decorative layer.

Thus, in certain embodiments, a mucoadhesive layer structure according to the invention comprises an additional muco-contact layer. In other embodiments, mucoadhesive layer structures according to the present invention do not include an additional muco-contact layer. In such embodiments, but also in certain other embodiments, the agomelatine-containing layer can be mucoadhesive. The additional mucosal contact layer, if present, is mucoadhesive and provides (improved) adhesion between the mucoadhesive layer structure and the patient's mucosa during administration. A mucosal contact layer is provided immediately below the active agent-containing layer, thus forming an adhesive layer between the mucosa and the agomelatine-containing layer during administration. Considering manufacturing convenience and overall patch size limitations, the size of the agomelatine-containing layer and the size of the mucosal contact layer are preferably coextensive.

As indicated above, the mucoadhesive layer construction may also include a decorative layer. In another embodiment, the mucoadhesive layer structure does not include a decorative layer.

In contrast to the mucosal-contacting layer, the decorative layer is positioned over the agomelatine-containing layer or over the backing layer and is not (necessarily) intended to contact the mucous membrane.

As a result, in some particular embodiments, the mucoadhesive layer structure comprises:
may further comprise one or more additional layers selected from A) a mucosal contact layer, and B) a decorative layer;
If different layers are present, the order is as follows.
decorative layer backing layer agomelatine-containing layer mucosal contact layer.

The decorative layer may provide a decorative means such as coloring or imprinting, or may simply prevent the patient from touching the backing as well as the agomelatine-containing layer during administration of the transmucosal therapeutic system. For such protective function, it is preferred that the decorative layer completely covers the backing layer and the agomelatine-containing layer. Thus, in certain embodiments, the mucoadhesive layer structure further comprises a decorative layer, wherein the size of the backing layer and the size of the decorative layer are coextensive, or the decorative layer is larger in size than the backing layer, surface area is expanded.

On the other hand, the decorative layer should not be confused with the backing layer. The decorative layer dissolves rapidly, and in certain embodiments, the decorative layer is dissolved in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for less than 3 minutes, less than 1 minute. , or dissolves in less than 30 seconds. The entire mucoadhesive layer structure is, in certain embodiments, soaked in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for 10 minutes or more, preferably 15 minutes or more, More preferably 30 minutes or more, or 15 hours or less, preferably 12 hours or less, more preferably 10 hours or less, or between 10 minutes and 15 hours, preferably between 15 minutes and 12 hours, more preferably between 30 minutes and Dissolves in 10 hours.

For ease of manufacture and for simplicity, in certain preferred embodiments, the transmucosal therapeutic system of the present invention does not include a mucosal contact layer or a decorative layer. Thus, in particular, the mucoadhesive layer structure can simply consist of a backing layer and an agomelatine-containing layer.

Thus, according to certain embodiments of the present invention, the transmucosal therapeutic system may further comprise a mucoadhesive overlay, or no mucoadhesive overlay, preferably no mucoadhesive overlay. This mucoadhesive overlay is specifically larger than the agomelatine-containing mucoadhesive layer structure and adheres thereto to enhance the adhesion properties of the overall transmucosal therapeutic system. The area of the mucoadhesive overlay increases the overall size of the transmucosal therapeutic system, but does not increase the release area.

As also outlined above, the transmucosal therapeutic system consists of one or more laminae, and thus, in certain embodiments, the transmucosal therapeutic system is in the form of a film. Such films may have a circular, rectangular or square shape.

The film preferably has some thickness. Otherwise, it is difficult to incorporate the required amount of active material, and very thin films are not easy to manufacture, especially with regard to providing uniform thickness. Thus, in certain embodiments, the transmucosal therapeutic system is in the form of a thin film having an areal weight of at least 75 g/m ² , preferably at least 100 g/m ² , or more preferably at least 130 g/m ² . Alternatively, when thickened, the transmucosal therapeutic system is in the form of a thin film having a layer thickness of at least 50 μm, preferably at least 75 μm, more preferably at least 100 μm. On the other hand, a very thick film is perceived by the patient as a disturbing object in the oral cavity and is therefore disadvantageous in terms of patient compliance. Thus, in certain embodiments, the transmucosal therapeutic system is in the form of a thin film having an areal weight of 700 g/m ² or less, preferably 600 g/m ² or less, or more preferably 500 g/m ² or less. Alternatively, with respect to thickness, the transmucosal therapeutic system is in the form of a thin film having a layer thickness of less than 800 μm, preferably less than 700 μm, more preferably less than 550 μm. In a preferred embodiment, the transmucosal therapeutic system has an area weight of 75-700 g/m ² , preferably 100-600 g/m ² , or more preferably 130-500 g/m ² or 50-800 μm, preferably is in the form of a thin film with a layer thickness of 75-700 μm, more preferably 100-550 μm.

Transmucosal therapeutic systems according to the present invention are typically stored in seam-sealed pouches without further protective measures. However, the mucoadhesive layer structure may be placed on a removable protective layer (release liner), which is removed immediately prior to application to the oral mucosa of the patient. Thus, a transmucosal therapeutic system may or may not further include a release liner. Transmucosal therapeutic systems protected by release liners are also commonly stored in seam-sealed pouches. The packaging may be child safe and/or elderly friendly.

Agomelatine-Containing Layer As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer.

Furthermore, the agomelatine-containing layer
i) agomelatine; and ii) a first soluble film former.

The areal weight of the agomelatine-containing layer is one of the factors determining the amount of active substance. A certain thickness is necessary to obtain a sufficient amount of active agent, and it is difficult to coat very thin layers, especially with sufficient precision. On the other hand, thick layers can not only cause discomfort in the oral cavity, but can also be difficult to manufacture and can result in too long to dissolve for the desired release profile. Upon consideration, the agomelatine-containing layer has an areal weight of at least 25 g/m ² , more preferably at least 35 g/m ² , or most preferably at least 40 g/m ² , or no greater than 300 g/m ² , more preferably have an area weight of 250 g/m ² or less, or most preferably 200 g/m ² or less, or between 25 and 300 g/m ² , more preferably between 35 and 250 g/m ² , or most preferably between 40 and 200 g/m ² preferably have an area weight of With respect to the thickness of the agomelatine-containing layer, the agomelatine-containing layer has a layer thickness of at least 15 μm, preferably at least 25 μm, more preferably at least 35 μm, or less than 550 μm, preferably less than 400 μm, more preferably less than 300 μm. It is preferred to have a layer thickness.

In transmucosal therapeutic systems that include a backing layer, active agent delivery is controlled by direct transmucosal delivery as described above, which in preferred embodiments is the area of release, i.e., the surface area of the agomelatine-containing layer, to control the effective dose. This is why it plays a decisive role in A certain minimum size is required to ensure that the patch does not prematurely detach from the mucosa and to be able to contain sufficient amounts of active agent without having to use very thick films. is. On the other hand, if the release area is too large, the transmucosal therapeutic system becomes bulky in size, uncomfortable to apply and wear, and reduces patient compliance. With this in mind, in certain embodiments of the present invention, the transmucosal therapeutic system has an emission area of at least 0.1 cm ² , preferably at least 0.2 cm ² , or more preferably at least 0.5 cm ² . or has an emission area of 10 cm ² or less, preferably 7 ^{cm 2} or less, or more preferably 5 cm ² or less ^; It has an emission area of 5-5 cm ² .

As also outlined above, and without wishing to be bound by theory, a sufficient amount of active agent contained in the transmucosal therapeutic system is sufficient to achieve certain properties of the transmucosal therapeutic system according to the present invention, such as good in vitro penetration. considered necessary to achieve certain advantageous characteristics. On the other hand, if the amount of active substance is too high, it can lead to undesirable storage stability problems such as recrystallization of the active substance when agomelatine is present in dissolved form, as well as excessive drug concentration in the oral cavity. can bring potential stimulating sensations to The amount of agomelatine contained in the transmucosal therapeutic system can be controlled in two ways by adjusting the concentration and/or areal weight of the agomelatine-containing layer. Details regarding areal weight are as outlined above. In terms of concentration, the agomelatine-containing layer comprises at least 1% by weight agomelatine, preferably at least 2% by weight agomelatine, more preferably at least 3% by weight agomelatine, or the agomelatine-containing layer is not more than 25% by weight agomelatine. , preferably 20% by weight or less of agomelatine, more preferably 10% by weight or less of agomelatine, or the agomelatine-containing layer comprises 1 to 25% by weight of agomelatine, preferably 2 to 20% by weight of agomelatine, and more It preferably contains 3 to 10% by weight or less of agomelatine.

Thus, in certain embodiments of the present invention, the agomelatine-containing layer provides at least 0.1 mg/cm ² , preferably at least 0.2 mg/cm ² , or more preferably at least 0.4 mg/cm ² per release area. The layer comprising or containing agomelatine of 2.0 mg/cm ² or less, preferably 1.5 mg/cm ² or less, or more preferably 1.2 mg/cm ² or less of agomelatine or containing agomelatine The layer comprises 0.1-2.0 mg/cm ² , preferably 0.2-1.5 mg/cm ² or more preferably 0.4-1.2 mg/cm ² of agomelatine.

With respect to the amount of active substance, the mucoadhesive layer structure contains at least 0.1 mg, preferably at least 0.2 mg, or more preferably at least 0.4 mg of agomelatine, or no more than 20 mg, preferably no more than 15 mg, or more preferably It may contain 10 mg or less of agomelatine, or 0.1 mg to 20 mg, preferably 0.2 mg to 15 mg, or more preferably 0.4 mg to 10 mg of agomelatine.

As outlined in more detail above, the correct dissolution behavior of the agomelatine-containing layer is very important for controlling the delivery route. The agomelatine-containing layer should dissolve/disintegrate quickly enough to ensure fast active substance release. Thus, the agomelatine-containing layer is, for example, in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for less than 5 hours, preferably less than 3 hours, more preferably less than 2 hours, most It preferably dissolves in less than 1 hour. However, if the agomelatine-containing layer dissolves much faster than it actually penetrates transmucosally, there is a risk that the dissolved material will leak into the saliva and that the backing layer will delaminate. Therefore, too rapid dissolution increases the risk of unintentionally swallowing a substantial portion of the active substance. So-called "flash wafers" are films designed to disintegrate very quickly to achieve enteral delivery and swallowing is intentional (easier when compared to tablets). The transmucosal therapeutic system of the present invention differs from flash wafers by its delivery mechanism, which typically takes longer to dissolve than flash wafers. In the specific situation of agomelatine as active substance, high concentrations of active substance are also undesirable due to the risk of irritating sensations. This is another reason why the dissolution is preferably not too fast. Thus, the agomelatine-containing layer is, for example, in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for more than 5 seconds, preferably more than 30 seconds, more preferably more than 1 minute, most It can preferably dissolve in more than 2 minutes. In a preferred embodiment, the agomelatine-containing layer is soaked in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for more than 5 seconds and less than 5 hours, preferably more than 30 seconds and less than 3 hours, more It dissolves preferably in more than 1 minute and less than 2 hours, most preferably in more than 2 minutes and less than 1 hour.

In certain preferred embodiments of the invention, the agomelatine-containing layer is mucoadhesive, as it is preferred that the agomelatine-containing layer can adhere directly to mucous membranes.

As can be appreciated in more detail below, in certain embodiments, the coating composition for preparing the agomelatine-containing layer preferably uses ethanol, but not water, as a solvent. Thus, an agomelatine-containing layer according to the present invention may be obtainable (and/or obtained) by drying a coated coating composition comprising agomelatine, a soluble film former, and ethanol. On the other hand, certain soluble film formers have high solubility in water but limited solubility in other solvents. Therefore, using water as a solvent also has the advantage that an agomelatine-containing layer can be obtained by drying a coated coating composition comprising agomelatine, a soluble film former, and water. reason for obtaining (and/or being obtained). A combination of ethanol and water is also possible, i.e. the agomelatine-containing layer may also be obtainable by drying a coated coating composition comprising agomelatine, a soluble film former, ethanol and water (and/or or obtained). Regarding the amount of water, the agomelatine-containing layer can be obtained by drying a coated coating composition containing less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water. can be (and/or obtained).

Considering the stability of the agomelatine-containing layer with respect to its composition, it is preferred that the agomelatine-containing layer does not contain volatile constituents that risk evaporating and altering the composition upon storage. Thus, in certain embodiments, the agomelatine-containing layer is substantially free of volatile solvents. Volatile solvents in this sense may be selected from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane and any mixture thereof, preferably C1-C3 linear and Selected from the group consisting of branched chain alcohols, ethyl acetate, hexane, n-heptane, and any mixture thereof. Considering that the transmucosal therapeutic system is applied intraorally, volatile solvents particularly include solvents that should not be digested, such as methanol, ethyl acetate, hexane, n-heptane, and mixtures thereof. be In particular, the agomelatine-containing layer comprises 5% or less, preferably 3% or less, more preferably 1% or less by weight of volatile solvent.

Due to the low solubility of agomelatine in water, substantial amounts of water in the agomelatine-containing layer carry the risk of recrystallization when the active substance is present in solution. Thus, in certain embodiments, the agomelatine-containing layer is substantially free of water, eg, 12% or less, 8% or less, 5% or less, or 4% or less, by weight water.

Backing Layer As outlined in more detail above, transmucosal therapeutic systems according to the present invention include a mucoadhesive layer structure that includes a backing layer. In preferred embodiments, the backing layer comprises a second soluble film former.

The backing layer prevents (at least a substantial amount of) the active from dissolving in saliva, and thus in certain embodiments the time it takes for the backing layer to dissolve is at least (at least a substantial amount of) ) as long as it takes for the active substance to be delivered across the mucosa, eg as long as it takes for the active substance-containing layer to dissolve.

Thus, in certain embodiments, upon administration of the transmucosal therapeutic system to a human patient, the backing layer is maintained for 5 minutes or more, preferably 10 minutes or more, more preferably 15 minutes or more, or 12 hours or less, preferably 8 hours or less. hours or less, more preferably 4 hours or less, or between 5 minutes and 12 hours, preferably between 10 minutes and 8 hours, more preferably between 15 minutes and 4 hours.

The backing layer is soaked in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for 10 minutes or longer, preferably 15 minutes or longer, more preferably 30 minutes or longer, or 15 hours or shorter, preferably. dissolves in 12 hours or less, more preferably 10 hours or less, or between 10 minutes and 15 hours, preferably between 15 minutes and 12 hours, more preferably between 30 minutes and 10 hours.

With respect to size, the backing layer may in particular be of the same size as or larger than the agomelatine-containing layer. Thus, in certain embodiments, the size of the backing layer and the size of the agomelatine-containing layer are coextensive, while in other embodiments, the backing layer is larger in size and has a greater surface area than the agomelatine-containing layer. Expanding. A mucoadhesive layer structure having a backing layer and an agomelatine-containing layer of the same size is easier to manufacture as the bilayer sheet can be die cut to provide the mucoadhesive layer structure, while the backing layer is more compact than the agomelatine-containing layer. Large mucoadhesive layer structures are more difficult to manufacture, but also offer the advantage of less risk of leakage of the active substance, since the edges of the active substance-containing layer will also be covered by the backing layer.

The areal weight of the backing layer is important for controlling the dissolution behavior and function of the backing layer to protect the active from dissolving in saliva. In order to provide sufficient protection of the active substance as well as a sufficient dissolution time which should generally be at least as long as required for penetration of the active substance and therefore as long as the dissolution time of the agomelatine-containing layer, a certain thickness is required. Saga is necessary. In addition, it is also difficult to coat very thin layers, especially with sufficient precision. On the other hand, thick layers can not only cause discomfort in the oral cavity, but can also be difficult to manufacture and can result in taking too long to dissolve for desired (eg, overnight) application. Considered, the backing layer has an area weight of at least 50 g/m ² , more preferably at least 75 g/m ² , or most preferably at least 100 g/m ² , or no more than 400 g/m ² , more preferably 350 g ^/ m ² or less, or ^most preferably 300 g/m ² or ^less ; It preferably has an area weight.

As also outlined above and without wishing to be bound by theory, the use of a backing layer to prevent the dissolution of the active substance into the saliva may reduce the irritation induced by agomelatine in the oral cavity. Sensation would be eliminated or at least substantially reduced, thus leading to improved patient compliance. It should therefore be appreciated that the backing layer is substantially free of agomelatine, e.g. less than 1%, preferably less than 0.5%, more preferably less than 0.1%, most preferably 0.05% It preferably contains less than agomelatine.

The coating composition for preparing the backing layer may use various solvents such as ethanol or water. Thus, a backing layer according to the present invention may be obtainable (and/or obtained) by drying a coated coating composition comprising a second soluble film former and ethanol. On the other hand, certain soluble film formers have high solubility in water but limited solubility in other solvents. Therefore, using water as a solvent also has advantages, as the backing layer may be obtainable by drying a coated coating composition comprising a second soluble film former and water. (and/or obtained) reason. A combination of ethanol and water is also possible, i.e. the backing layer may also be obtainable by drying the coated coating composition comprising the second soluble film former, ethanol and water (and/or or obtained). With respect to the amount of water, the backing layer can be obtained by drying a coated coating composition containing less than 50 wt%, or less than 20 wt%, or less than 10 wt%, or less than 5 wt% water. may (and/or be obtained).

Considering the stability of the backing layer with respect to its composition, it is preferred that the backing layer is free of volatile constituents that risk evaporating and altering the composition upon storage. Thus, in certain embodiments, the backing layer is substantially free of volatile solvents. Volatile solvents in this sense may be selected from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane and any mixture thereof, preferably C1-C3 linear and Selected from the group consisting of branched chain alcohols, ethyl acetate, hexane, n-heptane, and any mixture thereof. Considering that the transmucosal therapeutic system is applied intraorally, volatile solvents particularly include solvents that should not be digested, such as methanol, ethyl acetate, hexane, n-heptane, and mixtures thereof. be In particular, the backing layer comprises 5 wt% or less, preferably 3 wt% or less, more preferably 1 wt% or less of volatile solvents.

As outlined above, since agomelatine has low solubility in water, substantial amounts of water in the agomelatine-containing layer carry the risk of recrystallization when the active substance is present in solution. Since water present in the backing layer can migrate to the agomelatine-containing layer, in certain embodiments, the backing layer, particularly the transmucosal therapeutic system together, is substantially free of water, e.g. Contains wt% or less, 8 wt% or less, 5 wt% or less, or 4 wt% or less.

Agomelatine According to the present invention, the mucoadhesive layer structure contains agomelatine in a therapeutically effective amount, and the mucoadhesive layer structure comprises an agomelatine-containing layer.

According to the present invention, the active agent agomelatine is incorporated into the transmucosal therapeutic system, particularly the agomelatine-containing layer, in any form, i.e. in its free, dissociated or any associated form, such as hydrates, solvates, etc. , and in the form of particles, which may be in micronized form, in crystalline form, and in particular in one of the polymorphic forms thereof, and/or in amorphous form, and in any hybrid form of any of the foregoing forms or mixtures thereof. Although it may be present, it is preferred that agomelatine is present in free, dissociated form.

Further, in certain embodiments, agomelatine is present in the agomelatine-containing layer in dissolved form, dispersed form, crystalline form, particularly one of its polymorphic forms, amorphous form, hydrates, solvates, forms as described above. or as mixtures thereof.

In certain embodiments, the agomelatine-containing layer comprises agomelatine in dissolved form, dispersed form, crystalline form, particularly one of its polymorphic forms, amorphous form, hydrates, solvates, any of the forms previously described. It can be obtained (and/or obtained) by incorporating as hybrid forms or mixtures thereof.

The agomelatine in the agomelatine-containing layer may be (completely) dissolved or the agomelatine-containing layer may comprise agomelatine particles preferably composed of agomelatine in its free, dissociated form, such that the agomelatine is in dispersed form. exist. Of course, if the agomelatine is present in dispersed form, the agomelatine-containing layer may still contain the agomelatine in dissolved form, depending on the solubility of the active substance in the agomelatine-containing layer (eg, saturated or supersaturated).

In preferred embodiments, the agomelatine is completely dissolved, e.g., at least 90 mol %, preferably at least 95 mol %, more preferably at least 98 mol % or most preferably at least 99 mol % of agomelatine in the agomelatine-containing layer, It exists in dissolved form. It is also preferred that the agomelatine-containing layer does not contain agomelatine crystals.

As outlined above, the amount of agomelatine in transmucosal therapeutic systems is believed to be important for good release of the active agent and can be adjusted, for example, by agomelatine concentration. Thus, in certain embodiments, the concentration of agomelatine in the agomelatine-containing layer is 1-25% by weight of the agomelatine-containing layer, preferably 2-20% agomelatine, more preferably 3-10% by weight of the agomelatine-containing layer. Agomelatine range.

In certain embodiments, agomelatine has a purity of at least 95%, preferably at least 98%, more preferably at least 99% as determined by quantitative HPLC. Quantitative HPLC can be performed on reverse phase HPLC with UV detection. Specifically, when HPLC is performed isocratically, the following conditions can be used:
Column: RP octadecyl phase XTerra RP18 100 mm x 3.9 mm; 3.5 μm or equivalent Mobile phase _: 0.06 molar _KH2PO4 buffer/acetonitrile (60:40; v:v); pH 2.5
Gradient: isocratic Flux: 1.0 ml
Injection volume: 20 μL
Column temperature: 23°C
Wavelength: 229nm and 275nm
Run time: 5 minutes

The transmucosal therapeutic system according to the present invention advantageously exhibits improved stability with respect to agomelatine content as well as agomelatine degradation.

Thus, in certain embodiments, the agomelatine-containing layer initially (i.e., immediately after manufacture, e.g., within one week) contains at least 95%, preferably at least 97%, of the theoretical amount of agomelatine contained in the agomelatine-containing layer. %, more preferably at least 98%, even more preferably at least 99% of agomelatine. The theoretical amount of agomelatine is calculated from the amount of agomelatine used in the coating composition and the (actual) areal weight of the coated and dried agomelatine-containing layers of the transmucosal therapeutic systems tested.

The agomelatine-containing layer also initially contains less than 0.5%, preferably less than 0.2%, more preferably less than 0.1%, even more preferably less than 0.05% total agomelatine-related degradants. can.

In certain other embodiments, transmucosal therapeutic systems according to the present invention are stable upon storage, i.e., they may maintain initial agomelatine content values or exhibit minor degradation products. , which is as follows.

In one such embodiment, the agomelatine-containing layer is maintained at 25° C. and 60% relative humidity for at least 3 months, preferably for at least 6 months, more preferably for at least 9 months, and most preferably for at least 12 months. It contains agomelatine in an amount of at least 95%, preferably at least 97%, more preferably at least 98%, even more preferably at least 99% of the theoretical amount of agomelatine contained in the agomelatine-containing layer after being stored for months.

The agomelatine-containing layer also has a 0.5 %, preferably less than 0.2%, more preferably less than 0.1%, even more preferably less than 0.05% total amount of agomelatine-related degradants.

In one such embodiment, the agomelatine-containing layer is stored at 40° C./75% RH for at least 3 months, preferably for at least 6 months, after which the theoretical amount of agomelatine contained in the agomelatine-containing layer is reduced. It contains agomelatine in an amount of at least 95%, preferably at least 97%, more preferably at least 98%, even more preferably at least 99%.

The agomelatine-containing layer also has less than 0.5%, preferably less than 0.2%, more preferably less than 0.1% after storage at 40°C/75% RH for at least 3 months, preferably for at least 6 months. less than, even more preferably less than 0.05% total agomelatine-related degradants.

Methods for determining agomelatine content and total amount of agomelatine-related degradants, and adhesion and release forces are preferably performed as described for Examples 9a and 9c.

First and Second Soluble Film-Forming Agents As outlined above, the transmucosal therapeutic system according to the present invention comprises a backing layer and an agomelatine-containing layer comprising i) agomelatine and ii) a first soluble film-forming agent. wherein the backing layer preferably comprises a second dissolvable film former.

The first and (if present) second dissolvable film formers provide sufficient adhesion of the agomelatine-containing layer and backing layer so long as the transmucosal therapeutic system is kept dry. According to certain embodiments, the first dissolvable film former may also provide sufficient adhesion to the mucosa once wetted, ie, when in contact with the mucosa. In such embodiments, but also generally, the first dissolvable film former may be selected from mucoadhesive polymers. The second dissolvable film former may or may not be selected from mucoadhesive polymers.

Film formers are the primary control over the dissolution behavior of the agomelatine-containing layer and backing layer. This is why film formers are "soluble".

^In certain specific embodiments, the first ^soluble film former contains water, artificial or natural Dissolves in saliva, or any other aqueous medium at 37° C. and 150 rpm in less than 5 hours, preferably less than 3 hours, more preferably less than 2 hours, most preferably less. The first soluble film former may also be water, artificial or natural saliva, or any other aqueous medium when cast into a film having an areal weight of 30-100 g/m ² , or 50 g/m ² . at 37° C. and 150 rpm in more than 5 seconds, preferably in more than 30 seconds, more preferably in more than 1 minute and most preferably in more than 2 minutes. Of note, the first soluble film former also preferably lasts more than 5 seconds and less than 5 hours when cast into a film having an areal weight of 30 to 100 g/m ² , or 50 g/m ² . can dissolve in more than 30 seconds and less than 3 hours, more preferably more than 1 minute and less than 2 hours, most preferably more than 2 minutes and less than 1 hour.

Film formers suitable as first and/or second soluble film formers according to the invention are, for example, polymers such as polyvinylpyrrolidone (commercially available as Kollidon® 30F from BASF), methylcellulose (Colorcon (commercially available as Methocel® from Colorcon), ethyl cellulose (commercially available as Ethocel® from Colorcon), hydroxyethyl cellulose (commercially available as Natrosol® 250L from Ashland Industries), hydroxypropyl Cellulose (commercially available as Klucel® from Ashland Industries), hydroxypropyl methylcellulose (also known as hypromellose, commercially available as Pharmacoat® from Shin-Etsu), sodium carboxymethylcellulose (a uncrosslinked sodium salt, also known as CMC or carmellose, commercially available as Blanose® from Ashland Industries), polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers (as Soluplus® from BASF). commercially available), polyvinyl alcohol (commercially available from Kuraray as Mowiol® 4-88), polyvinyl alcohol-polyethylene glycol copolymer (commercially available from BASF as Kollicoat® IR), polyvinylpyrrolidone - polyvinyl acetate copolymer (also called copovidone, commercially available as Kollidon® VA64 from BASF), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer (Evonik Eudragit® L100, Eudragit ( L12,5, Eudragit® S100 and Eudragit® S12,5), and methacrylic acid-ethyl methacrylate copolymers (Evonik from Eudragit® L100-55 and Eudragit® S12,5). ® L30D55), as well as natural film formers , for example shellac, pectin, gelatin, alginates, pullulan and starch derivatives, and any mixtures thereof.

Not only can the first and second soluble film formers provide sufficient adhesion to the agomelatine-containing layer and the backing layer, but preferably the patient can touch and manipulate the agomelatine-containing layer and the backing layer to For example, it should also be possible to provide a film that is not tacky in the dry state so that a transmucosal therapeutic system containing these layers can be applied to the oral mucosa without sticking it to the finger. In addition, the first and second dissolving film formers are the primary control over the dissolution behavior of the agomelatine-containing layer and the backing layer, which should not be too fast or too slow, so Or the second soluble film former is preferably soluble, dispersible or otherwise disintegratable in an aqueous medium, specifically saliva or simply water. On the one hand, with respect to ease of manufacture and to allow a water-free manufacturing process, which is advantageous in avoiding crystals or recrystallization of the active agent, C1-C3 alcohols Also preferred are film formers that are soluble in other solvents such as, in particular ethanol. It is therefore particularly preferred that the film-forming agent (first or second) is soluble in both water and ethanol, although high solubility may lead to too rapid dissolution of the agomelatine-containing layer. Therefore, the selection of film formers is not a trivial task.

In view of the above, the inventors have surprisingly found that polymers such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl methacrylate copolymer, and any mixtures thereof, the first of soluble film formers. It is particularly preferred that the first soluble film former is hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose. The second soluble film former, on the other hand, is preferably a mixture of hydroxyethylcellulose and hydroxypropylcellulose.

Hydroxypropyl cellulose is commercially available from Ashland under the brand name Klucel™ and comes in several grades.

The grades differ by molecular weight MW (determined by GPC size exclusion chromatography) and Brookfield viscosity (25° C., LVF, no moisture) and are as follows:
HF grades have a MW of 1,150,000 and a Brookfield viscosity of 1500-3000 (1% in water),
The MF grade has a MW of 850,000 and a Brookfield viscosity of 4000-6500 (2% in water),
GF grade has a MW of 370,000 and a Brookfield viscosity of 150-400 (2% in water)
The JF grade has a MW of 140,000 and a Brookfield viscosity of 150-400 (5% in water)
The LF grade has a MW of 95,000 and a Brookfield viscosity of 75-150 (5% in water),
EF grade has a MW of 80,000 and a Brookfield viscosity of 300-600 (10% in water)
ELF grades have a MW of 40,000 and a Brookfield viscosity of 150-300 (10% in water).

Thus, in certain embodiments, the hydroxypropylcellulose has a molecular weight of 30,000 to 1,500,000 (as determined by GPC size exclusion chromatography), particularly the hydroxypropylcellulose
Between 35,000 and 45,000, especially 40,000
Between 75,000 and 85,000, especially 80,000
Between 90,000 and 100,000, especially 95,000
Between 130,000 and 150,000, especially 140,000
between 350,000 and 400,000, especially 370,000,
having a molecular weight (determined by GPC size exclusion chromatography) selected between 800,000 and 900,000, especially 850,000 and between 1,100,000 and 1,200,000, especially 1,150,000 .

In view of the above, in certain preferred embodiments, the first soluble film former is selected from hydroxypropylcellulose, or hydroxypropylcellulose and ethylcellulose having a molecular weight of 50,000 to 1,500,000. more preferably the first soluble film former is hydroxypropyl cellulose or between 75,000 and 85,000, especially 80,000
Between 90,000 and 100,000, especially 95,000
selected from hydroxypropylcellulose and ethylcellulose having a molecular weight selected between 350,000 and 400,000, especially 370,000, and between 1,100,000 and 1,200,000, especially 1,150,000 It is a mixture of one or more polymers. Most preferably the first soluble film former is hydroxypropylcellulose having a molecular weight between 90,000 and 100,000, especially 95,000, or between 75,000 and 85,000, especially 80,000. 000 molecular weight, a mixture of one or more polymers selected from hydroxypropylcellulose with a molecular weight between 350,000 and 400,000, especially 370,000, and ethylcellulose, especially 75,000 a mixture of hydroxypropylcellulose with a molecular weight of between 85,000, especially 80,000 and hydroxypropylcellulose with a molecular weight of between 350,000 and 400,000, especially 370,000, or between 75,000 and 85,000 , especially a mixture of hydroxypropyl cellulose with a molecular weight of 80,000, and ethyl cellulose.

Also in certain preferred embodiments, the second soluble film former comprises hydroxyethyl cellulose and a molecular weight of 50,000 to 1,500,000, especially
Between 75,000 and 85,000, especially 80,000
Between 90,000 and 100,000, especially 95,000
a mixture of hydroxypropylcelluloses having a molecular weight selected between 350,000 and 400,000, especially 370,000, and between 1,100,000 and 1,200,000, especially 1,150,000, and more Preferably, the second soluble film former is a mixture of hydroxyethylcellulose and hydroxypropylcellulose having a molecular weight between 75,000 and 85,000, especially 80,000. Herein, the ratio of hydroxyethyl cellulose and hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, especially 80,000 is preferably 1:2 to 8:1, more preferably 1:1. ~4:1, most preferably 2:1.

Polyvinylpyrrolidone is preferably soluble polyvinylpyrrolidone.

The term "soluble polyvinylpyrrolidone" is used at least in ethanol, preferably water, diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene. Refers to polyvinylpyrrolidone, also known as povidone, which is more than 10% soluble in glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of commercially available polyvinylpyrrolidones include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90 from BASF. F, or Povidone K90F. Different grades of Kollidon® are defined in terms of K values that reflect the average molecular weight of polyvinylpyrrolidone grades. Kollidon® 12 PF is characterized by a K-value range of 10.2-13.8, which corresponds to a nominal K-value of 12. Kollidon® 17 PF is characterized by a K-value range of 15.3-18.4, which corresponds to a nominal K-value of 17. Kollidon® 25 is characterized by a K-value range of 22.5 to 27.0, corresponding to a nominal K-value of 25, and Kollidon® 30 is characterized by a K-value range of 27.0, corresponding to a nominal K-value of 30. ~32.4. Kollidon® 90 F is characterized by a K-value range of 81.0-97.2, which corresponds to a nominal K-value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30, and Kollidon® 90 F. For all grades and types of polyvinylpyrrolidone it is preferred that the amount of peroxide is within certain limits, in particular the amount of peroxide is 500 ppm or less, more preferably 150 ppm or less, most preferably 100 ppm. It is below.

Within the meaning of the present invention, the term "K value" refers to the value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and USP monograph for "povidone" .

Thus, in certain embodiments, polyvinylpyrrolidone is
9 to 15, preferably 10.2 to 13.8,
15 to 20, preferably 15.3 to 18.4,
20 to 27, preferably 22.5 to 27.0,
27-35, preferably 27.0-32.4, and 75-110, preferably 81.0-97.2,
polyvinylpyrrolidone having a K value within the range selected from the group consisting of or any mixture thereof, more preferably within the range of 27.0 to 32.4 or 81.0 to 97.2 Polyvinylpyrrolidones with K values and any mixtures thereof, most preferably polyvinylpyrrolidones with K values in the range of 81.0 to 97.2.

A certain amount of the first and second soluble film formers should be included in order to be able to provide sufficient adhesion to the agomelatine-containing layer and the backing layer. Thus, in certain preferred embodiments, the amount of first soluble film former is at least 65%, more preferably at least 70%, and most preferably at least 75% by weight of the agomelatine-containing layer. On the other hand, the amount of the first soluble film former can also be 98% or less, 94% or less, or 90% or less by weight of the agomelatine-containing layer. In certain embodiments, the amount of the first soluble film former ranges from 65-98%, 70-94%, or 75-90% by weight of the agomelatine-containing layer. In certain preferred embodiments, the amount of second soluble film former is at least 65%, more preferably at least 75%, and most preferably at least 85% by weight of the backing layer. In certain embodiments, the amount of second soluble film former ranges from 65-100%, 75-100%, or 85-100% by weight of the backing layer.

Such film formers may be present as first and/or second soluble film formers in the agomelatine-containing layer and/or backing layer, but may be included in any overlay.

Additional Additives The agomelatine-containing layer and the backing layer of the transmucosal therapeutic system according to the present invention each contain fatty acids, sweeteners, flavorants, colorants, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers. , antioxidants, stabilizers, buffering agents and further film forming agents.

Such additives may be present in the agomelatine-containing layer in an amount of 0.001 to 15% by weight of the agomelatine-containing layer per additive. In certain embodiments, the total amount of all additives is 0.001-25% by weight of the agomelatine-containing layer. Hereinafter, when ranges of amounts for particular additives are provided, such ranges refer to the amount per individual additive.

It should be noted that in pharmaceutical formulations, formulation ingredients are categorized according to their physicochemical and physiological properties and according to their function. This means, in particular, that substances or compounds that fall into one category of pharmaceutical ingredients are not excluded from being classified into another category. For example, certain polymers can be crystallization inhibitors, but also tackifiers. Some substances, for example, can act as permeation enhancers as well as being typical emollients. A person skilled in the art can determine, based on his general knowledge, which category(es) of formulation components a particular substance or compound belongs to. Details of excipients and additives are provided below and should not be understood as exclusive. Other substances not explicitly listed herein may also be used according to the invention, and substances and/or compounds explicitly listed in one category of formulation ingredients may be used in the sense of the invention as another formulation ingredient. not excluded from use as

Given the potential stinging or irritating effects of agomelatine, substances that can mask or modify the taste or that may reduce the effects of agomelatine are particularly preferred. For example, researchers have shown that certain fatty acids can reduce capsaicin-induced effects such as pain/itch.

Thus, in certain preferred embodiments, the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents. The backing layer also preferably comprises one or more excipients selected from the group consisting of fatty acids, sweeteners and flavoring agents.

Fatty acids may in particular be saturated or unsaturated, linear or branched carboxylic acids containing from 4 to 24 carbon atoms, especially caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidin. acid, vaccenic acid, linoleic acid, linoleidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid. Especially preferred are oleic acid or linoleic acid.

In terms of amount, the agomelatine-containing layer and/or the backing layer preferably comprise one or more fatty acids in an amount of at least 1% by weight, more preferably at least 3% by weight, more preferably at least 4% by weight. The agomelatine-containing layer and/or the backing layer may also contain one or more fatty acids in an amount of 15% or less, preferably 12% or less, more preferably 10% or less by weight. Finally, the agomelatine-containing layer and/or the backing layer may also contain one or more fatty acids in an amount of 1-15% by weight, preferably 3-12% by weight, more preferably 4-10% by weight.

In certain preferred embodiments, the agomelatine-containing layer and/or backing layer comprises saccharose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin. , neotame, steviol glycosides, thaumatin and sodium saccharin. Particularly preferably, the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of saccharose, sucralose and sodium saccharin. In such particularly preferred embodiments, i.e. when the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucralose, saccharose and sodium saccharin, the amount of each sweetener is at least 0. .05 wt%, preferably at least 0.1 wt%, more preferably at least 0.3 wt%, and/or 2.0 wt% or less, preferably 1.5 wt% or less, more preferably 1.0 wt% or less. 0% by weight or less and/or 0.05 to 2.0% by weight, preferably 0.1 to 1.5% by weight, more preferably 0.3 to 1.0% by weight.

Also in preferred embodiments, the agomelatine-containing layer and/or backing layer comprises vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, one or more natural or artificial flavors selected from the group consisting of ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin and eucalyptol, and flavoring compositions such as peppermint flavor including. Vanillin, methyl salicylate, menthol, peppermint flavor and eucalyptol are particularly preferred. In such particularly preferred embodiments, i.e. when the agomelatine-containing layer and/or the backing layer comprises one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavor and eucalyptol, The amount of flavoring agents is each at least 0.1 wt%, preferably at least 0.3 wt%, more preferably at least 0.4 wt%, and/or no more than 10 wt%, preferably no more than 6 wt%. , more preferably not more than 4% by weight, and/or 0.1-10% by weight, preferably 0.3-6% by weight, more preferably 0.4-4% by weight, or the total at least 0.1 wt%, preferably at least 0.5 wt%, more preferably at least 0.7 wt%, and/or no more than 15 wt%, preferably no more than 10 wt%, more preferably 8 wt% % or less and/or 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 0.7 to 8% by weight. Suitable flavoring agents are also commercially available from Mane, Inc., and apple, caramel, chocolate, lemon, mint, or any of those identified by tonality can be used as flavoring agents in the present invention.

In certain embodiments, the agomelatine-containing layer and/or the backing layer comprise one or more colorants. Any colorant suitable for use in pharmaceutical/food applications can be included, particularly colorants approved for use by the US FDA or European Agencies EFSA/EMA. Such colorants are, for example, titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5′-phosphate, quinoline yellow, orange yellow S , cochineal, carminic acid, azorubin, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotine, chlorophyll, chlorophyllin, copper complex of chlorophyll and chlorophyllin, green S, plain caramel, caustic sulfite caramel, ammonia caramel, monkey Phytoammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotene, annatto, bixin, norbixin, paprika extract, capsancyan, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, It may be selected from the group consisting of beetroot red, betanin, anthocyanin, calcium carbonate, iron oxides and hydroxides, aluminum, silver, gold and lysol rubin BK.

The agomelatine-containing layer and/or backing layer may comprise one or more additional film formers in addition to those disclosed for soluble film formers above. Such additional film formers are different from those previously disclosed for soluble film formers. Thus, in certain embodiments, the agomelatine-containing layer and/or backing layer comprises one or more additional film formers in addition to those disclosed for the first and second soluble film formers above. include. Such additional film formers are different from those previously disclosed for soluble film formers. The one or more additional film formers are present in the agomelatine-containing layer and/or the backing layer in an amount of at least 2%, preferably at least 5%, more preferably at least 10% and/or 40% by weight, respectively. % or less, preferably 30 wt% or less, more preferably 25 wt% or less, and/or an amount of 2 to 40 wt%, preferably 5 to 30 wt%, more preferably 10 to 25 wt%, and/ or in total an amount of at least 5 wt%, preferably at least 15 wt%, more preferably at least 20 wt%, or an amount of 40 wt% or less, preferably 30 wt% or less, more preferably 25 wt% or less, and /or in an amount of 5-40% by weight, preferably 15-30% by weight, more preferably 20-25% by weight.

In certain embodiments, the agomelatine-containing layer and/or the backing layer comprise one or more solubilizers. Suitable solubilizers are, for example, ethoxylated sorbitans esterified with fatty acids, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate. ate (commercially available as Tween 80 or polysorbate 80), safflower oleosomes, propanediol and polyethoxylated castor oil. Such solubilizers are present in the agomelatine-containing layer and/or backing layer, respectively, in an amount of at least 1%, preferably at least 3%, more preferably at least 5% by weight and/or no more than 25% by weight, preferably It may be included in an amount of 20 wt.% or less, more preferably 15 wt.% or less, and/or in an amount of 1-25 wt.%, preferably 3-20 wt.%, more preferably 5-15 wt.%.

The agomelatine-containing layer and/or the backing layer may also contain one or more emulsifiers. Such emulsifiers are commercially available, for example, soy lecithin, sodium phosphate, mono- and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric esters of mono- and diglycerides, and polyethoxylated hydrogenated castor oil (BASF as Chremophor RH 40). ). The emulsifier is, for example, in the agomelatine-containing layer and/or the backing layer, respectively, in an amount of at least 1% by weight, preferably at least 3% by weight, more preferably at least 5% by weight, and/or no more than 25% by weight, preferably 20% by weight. % or less, more preferably 15% or less, and/or 1-25%, preferably 3-20%, more preferably 5-15%.

In certain embodiments, the agomelatine-containing layer and/or the backing layer comprise one or more plasticizers. The one or more plasticizers are monosaccharides, disaccharides, oligosaccharides and polysaccharides and derivatives such as sorbitol (commercially available from Cargill as Sorbidex™), polyethylene glycol, triacetin, triethyl citrate, propylene It may be selected from the group consisting of glycol, glycerol and medium chain triglycerides. The agomelatine-containing layer and/or the backing layer each contain one or more plasticizers in an amount of at least 0.5% by weight, preferably at least 1% by weight, more preferably at least 5% by weight, and/or 25% by weight. % or less, preferably 20 wt % or less, more preferably 15 wt % or less, and/or in an amount of 0.5 to 25 wt %, preferably 1 to 20 wt %, more preferably 5 to 15 wt % can contain.

The agomelatine-containing layer may also contain a permeation enhancer. In one embodiment, the agomelatine-containing layer comprises diethylene glycol monoethyl ether (transcutol), dipropylene glycol, levulinic acid, lauryl lactate, lactic acid, dimethylethylene urea, N,N'-dimethylpropylene urea DMPU and N,N-diethyl - meta-toluamide (DEET), 2-(2-ethoxyethoxy)ethanol, 2,5-dimethylisosorbide (Dotisol), propylene glycol monocaprylat, 2-methoxy-4-(prop-2-en-1-yl) ) a permeation enhancer selected from the group consisting of phenol and laurocapram. Such permeation enhancers are present in the agomelatine-containing layer in an amount of at least 1 wt%, preferably at least 2 wt%, more preferably at least 5 wt%, and/or no more than 20 wt%, preferably no more than 15 wt%, More preferably, it may be included in an amount of 10 wt.% or less, and/or in an amount of 1-20 wt.%, preferably 2-15 wt.%, more preferably 5-10 wt.%.

On the other hand, certain compounds that can be considered permeation enhancers are not preferred. Thus, in some embodiments, the agomelatine-containing layer contains bile acids, bile salts, bile acid derivatives, acylcarnitines, sodium dodecyl sulfate, dimethylsulfoxide, sodium lauryl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, more than 5% by weight, preferably more than 1% by weight, more preferably more than 0.2% by weight, most preferably more than 0.2% by weight of a permeation enhancer selected from the group consisting of saponin derivatives, chitosan, EDTA, citric acid, and salicylates; Not contained in amounts greater than 0.1% by weight.

The agomelatine-containing layer according to the invention may contain a pH adjusting agent. Preferably, the pH adjuster is a buffer containing a mixture of mono- and polytropic acids, mono-, di- and tri-acids, weak acid bases and their conjugate bases, respectively, amine derivatives , inorganic alkali derivatives, polymers with basic and acidic functionalities.

Release Characteristics The transmucosal therapeutic system according to the present invention is designed to transmucosally administer certain amounts of agomelatine into the systemic circulation, particularly at night.

Administration of the transmucosal therapeutic system of the present invention generally and preferably involves applying the mucoadhesive layer structure to the oral mucosa of a human patient (after removal of any eventual release liner) and dissolving it. It consists of maintaining on the mucosa until The site of application can be buccal, sublingual, gingival or palatal, i.e., in preferred embodiments, administration of the transmucosal therapeutic system will cause the mucoadhesive layer structure to spread to the buccal, sublingual, gingival or palatal mucosa, It preferably consists of applying to the buccal mucosa of the oral cavity of a human patient and maintaining it on the mucosa until it dissolves.

In a particular embodiment of the invention, a transmucosal therapeutic system according to the invention, as described above, has from 10 μg/cm ² -hr to 150 μg/cm ² -hr after 1 hour, as measured using porcine esophageal mucosa. Figure 3 provides mucosal permeation rates of agomelatine.

In certain embodiments, a transmucosal therapeutic system according to the present invention provides at least 0.02 mg/cm ² , preferably at least 0.05 mg/cm ² , more than 8 hours when measured using porcine esophageal mucosa. preferably at least 0.1 mg/cm ² and/or no more than 0.5 mg/cm ² , preferably no more than 0.4 mg/cm ² , more preferably no more than 0.3 mg/cm ² and/or 0.02 mg/cm It provides a cumulative release of agomelatine of ² to 0.5 mg/cm ² , preferably 0.05 mg/cm ² to 0.4 mg/cm ² , more preferably 0.1 mg/cm ² to 0.3 mg/cm ² .

Methods of Treatment/Medical Uses According to a particular aspect of the invention, the transmucosal therapeutic system according to the invention is for use in methods of treatment, particularly methods of treating a human patient. According to another aspect, the invention relates to a method of treatment, wherein a transmucosal therapeutic system according to the invention is administered to a human patient. In yet another aspect, the invention relates to the use of the transmucosal therapeutic system of the invention for the manufacture of a medicament for treatment, preferably for treatment of a human patient.

The majority of patients, more than 80% of those suffering from classic mood disorders (major depression, depressive phase of bipolar disorder, or generalized anxiety disorder), exhibit disturbed sleep-wake cycles and sleep architecture. . Characteristically, difficulty falling asleep (increased sleep onset latency) followed by intermittent sleep results in significant daytime sleepiness, which further impairs the ability to function properly in daily life and establishes a vicious cycle. There are no specific treatment guidelines for depression, but available options are generally based on the premise that depression and sleep disorders share a bidirectional relationship, so that successful treatment of one condition The other state will also benefit from each other.

In recent years, circadian rhythm disturbances, the adaptive disorders and functions of not only core physiological functions such as body temperature and blood pressure, but also of the "body clock" that locks highly complex neurotransmitter responses to the time of day Disorder has emerged as a major contributor to major depressive disorder requiring therapeutic attention. Dysfunction of the connection between the suprachiasmatic nucleus, the pineal gland and the neurohormone (melatonin) it produces has been suggested as a major cause of these phenomena. Melatonin has been strongly advocated (and marketed) as a "non-light circadian rhythm resynchronizer" for treating jet lag and insomnia associated with shift work, and the antidepressant and anxiolytic effects of melatonin have been investigated. Many have been published. Due to the low oral bioavailability of melatonin, synthetic melatonin receptor agonists have been investigated. The most prominent of these is agomelatine.

Agomelatine is approved for the treatment of depression, but has been suggested for the treatment of other indications such as bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia and OCD.

Thus, in certain embodiments, transmucosal therapeutic systems according to the present invention are preferably for use in methods of treating major depression. Similarly, in certain other embodiments, the invention relates to methods of treating major depression, wherein transmucosal therapeutic systems according to the invention are administered to human patients. In still other embodiments, the invention relates to the use of the transmucosal therapeutic system of the invention for the manufacture of a medicament for treating major depression.

Treatment of depression, or major depression, aka major depressive disorder, includes conditions in patients with depression/MDD, such as major depressive episodes, anxiety symptoms, sleep-wake cycle disturbances, daytime sleepiness and insomnia. (the majority of MDD patients, ie, over 80%, suffer from depression combined with insomnia). In other embodiments, treatment may also generally refer to treatment of bipolar disorder, generalized anxiety disorder, Smith-Magenis syndrome, periventricular leukomalacia, or OCD.

As outlined above, transmucosal delivery avoids the first pass effect and therefore transmucosal therapeutic systems according to the present invention have a reduced risk of hepatotoxicity, unlike oral agomelatine dosage forms. Therefore, there are no restrictions regarding the patient group to be treated. Treatment includes treatment of human patients with or without liver dysfunction, including patients with at least mild or at least moderate liver dysfunction.

Also, in certain embodiments, treatment with a transmucosal therapeutic system of the invention provides a reduction in at least one agomelatine-associated side effect compared to a comparable oral dose of agomelatine. As outlined above, in certain specific embodiments, such agomelatine-associated side effect is hepatotoxicity. Comparisons with comparable oral doses of agomelatine should be understood as comparisons of the incidence and intensity of side effects in clinical studies when using transmucosal and oral agomelatine doses that yield substantially the same plasma exposure of agomelatine. be. The incidence of at least one agomelatine-related side effect is reduced by at least about 30%, preferably by at least about 40%, more preferably by at least about 70%, and most preferably by at least about 80% compared to a comparable oral dose of agomelatine and/or the intensity of at least one agomelatine-related side effect may be reduced compared to an equivalent oral dose of agomelatine. The intensity of a side effect can be determined, for example, by classifying the side effect on a scale indicating intensity as "mild," "moderate," or "severe," and reductions in intensity are quantified by comparing median intensities. can be

In any of the treatments outlined for the above aspects and embodiments, the transmucosal therapeutic system is preferably administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient, and is allowed to remain on the mucosa until dissolved. maintained. In a preferred embodiment, the transmucosal therapeutic system is administered by applying the mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient and remains on the mucosa until dissolution. In a more preferred embodiment, the transmucosal therapeutic system is administered in the evening or night before bed.

In another embodiment, a transmucosal therapeutic system according to the present invention may also be for use in a method of reducing at least one agomelatine-related side effect in a patient as compared to an equivalent oral dose of agomelatine.

The present invention also relates to a method of reducing at least one agomelatine-related side effect in a patient being treated with oral agomelatine therapy, the method comprising:
a) discontinuing oral agomelatine therapy; and b) administering a transmucosal therapeutic system according to the present invention to the mucous membranes of the oral cavity of a human patient, wherein the transmucosal therapeutic system compares to an equivalent oral dose of agomelatine. and provide relief of at least one agomelatine-related side effect.

In such methods, the transmucosal therapeutic system can deliver an amount of agomelatine equivalent to that originally provided by oral agomelatine therapy.

Manufacturing Process The present invention further relates to an agomelatine-containing layer for use in a transmucosal therapeutic system, and a corresponding mucoadhesive layer structure comprising the agomelatine-containing layer, and a manufacturing process for the corresponding transmucosal therapeutic system.

According to the present invention, the process for producing an agomelatine-containing layer comprises:
i) combining at least agomelatine and a first soluble film former in a solvent to obtain a first coating composition;
ii) coating the coating composition onto a release liner; and iii) drying the coated coating composition to form an agomelatine-containing layer.

In such processes, suitable first soluble film formers are the same as those described above.

In this manufacturing process, in step i), agomelatine may be dissolved or dispersed to obtain a coating composition.

It is preferred not to use water as agomelatine has poor solubility in water and therefore risks recrystallization. Therefore, in a preferred embodiment, the solvent does not contain water in an amount of more than 5 wt%, preferably more than 2 wt%, more preferably more than 1 wt%, most preferably more than 0.5 wt%. On the other hand, depending on the solubility of the soluble film formers used in different solvents, it may be advantageous to use water. Thus, in some embodiments the solvent comprises water.

Thus, in the above process, the solvent preferably comprises an alcoholic solvent selected from methanol, ethanol, isopropanol and mixtures thereof, more preferably the solvent comprises or consists of ethanol.

Preferences for the first soluble film former and other constituents of the agomelatine-containing layer are as outlined above. Thus, in one embodiment step i) comprises adding at least agomelatine, a first soluble film forming agent and one or more excipients selected from the group consisting of fatty acids, sweeteners and flavoring agents to combining in a solvent to obtain a coating composition. Also in step i) the agomelatine is dissolved, dispersed, crystalline, in particular in one of its polymorphic forms, in amorphous form, in hydrates, solvates, hybrid forms of any of the foregoing forms. or combined as a mixture thereof.

In step iii) drying is preferably carried out in one or more cycles at room temperature and/or at a temperature of 40-90°C, more preferably 60-80°C.

The agomelatine-containing layer, prepared as outlined above, is then supplemented with at least a backing layer to provide the transmucosal therapeutic system of the present invention.

Thus, in one first aspect, the invention also relates to a process for manufacturing a transmucosal therapeutic system, the process comprising:
A) producing an agomelatine-containing layer as outlined above,
B) a backing layer,
i) dissolving at least a second soluble film former in a solvent to obtain a second coating composition;
ii) coating a second coating composition onto a release liner; and iii) drying the second coated coating composition to form a backing layer; and C) Laminating the resulting agomelatine-containing layer and a backing layer.

In another second aspect, the present invention relates to a process for manufacturing a transmucosal therapeutic system, the process comprising:
A) producing an agomelatine-containing layer as outlined above,
B) a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer,
i) dissolving at least a second soluble film former in a solvent to obtain a second coating composition;
ii) coating a second coating composition onto the agomelatine-containing layer obtained in A); and iii) drying the second coated coating composition to form a backing layer coated onto the agomelatine-containing layer. comprising preparing by a process comprising the step of forming

In such a process according to the second aspect, step ii) of coating the second coating composition onto the agomelatine-containing layer is preferably performed at least once, in particular twice or three times.

In both the first and second aspects, in B) of the process, the solvent comprises one or more of an alcoholic solvent such as methanol, ethanol and isopropanol, and water, preferably the solvent is ethanol or consists of ethanol and/or the solvent comprises water.

Drying in such a process according to the first or second aspect is preferably carried out in one or more cycles at room temperature and/or at 40-90°C, more preferably 60-80°C, More preferably, drying is performed at a temperature of 40-90°C, or 60-80°C.

A mucoadhesive layer structure comprising an agomelatine-containing layer and a corresponding transmucosal therapeutic system can be packaged, for example, by sealing the individual transmucosal therapeutic system in a pouch of primary packaging material, as is known to those skilled in the art. Additional manufacturing steps such as stamping can be used to manufacture using the processes outlined above. Such further steps preferably result in a mucoadhesive layered structure or transmucosal therapeutic system as described in the previous section.

The present invention particularly relates to agomelatine-containing layers and mucoadhesive layer structures and transmucosal therapeutic systems obtainable (and/or obtained) by the processes described above.

The invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should not be construed as limiting the invention in any way. The numbers provided in the examples for amounts or area weights of ingredients in the compositions may vary slightly due to manufacturing variations.

Examples 1A-1F
Coating Compositions The formulations of the agomelatine-containing coating compositions of Examples 1a-1f are summarized in Table 1.1 below. As also shown in Table 1.1, formulations are based on weight percent.

Preparation of First Coating Composition (Agomelatine-Containing Layer) For Examples 1a-1f, a first beaker was filled with agomelatine. Approximately one-third of ethanol, eucalyptol, menthol, methyl salicylate, Novamint fresh peppermint, Colifer RH 40, FD&C Red No. 40, sucralose were added and then stirred. Polyvinylpyrrolidone was added under stirring. A second beaker was filled with distilled water. Polysorbate 80 was added and the mixture was then stirred. The remaining ethanol was added under stirring. The contents of the two beakers were mixed under stirring to give a slightly red solution with a visible crystalline precipitate.

Preparation of Second Coating Composition (Backing Layer) For Examples 1b-1f, ethanol was added to a beaker and then stirred. Ethylcellulose and castor oil were added under stirring to give a slightly opaque mixture.

The resulting backing composition was coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried at room temperature for approximately 10 minutes and 70° C. for 20 minutes. and dried. The coating thickness resulted in areal weights of 20.9 g/m ² (Examples 1b, 1e and 1f) and 20.8 g/m ² (Examples 1c and 1d).

After removing the release liner, the agomelatine-containing coating was applied to the backing layer.

Coating of the First Coating Composition The resulting agomelatine-containing first coating composition of Example 1a was coated on a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner). Coated on and dried for approximately 5 minutes at room temperature and 10 minutes at 50° C. (Example 1a). For Example 1a, the dry film is the final agomelatine-containing mucoadhesive layer structure.

The coating thickness resulted in an areal weight of 57.9 g/m ² (Example 1a).

The resulting agomelatine-containing first coating compositions of Examples 1b-1f were coated onto the dried backing layer, respectively, at room temperature for approximately 5 minutes, at 50° C. for 10 minutes, and at 90° C. for 4 minutes. (Examples 1b and 1f), approximately 5 minutes at room temperature and 10 minutes at 50°C (Example 1c), approximately 6 minutes at room temperature, 12 minutes at 50°C, and 4 minutes at 90°C. (Example 1d), and approximately 5 minutes at room temperature, 10 minutes at 50°C, and 2 minutes at 90°C (Example 1e).

The coating thicknesses were 57.9 g/m ² (Example 1a), 53.9 g/m ² (Example 1b), 34.9 g/m 2 (Example 1c), 72.9 g/m ² (Example 1c), respectively, for the agomelatine-containing layer. Resulting in areal weights of 1 g/m ² (Example 1d), 50.5 g/m ² (Example 1e), and 53.4 g/m ² (Example 1f).

Preparation of transmucosal therapeutic systems (for all examples)
Individual transmucosal therapeutic systems were then punched out of the agomelatine-containing mucoadhesive layered structures. This is because the OTF does not adhere well to the mucosa based solely on its physical properties and/or the agomelatine-containing layer has prominent corners (square or rectangular shape) to avoid waste. ). The transmucosal therapeutic system is then punched out and sealed in a pouch of primary packaging material under a protective atmosphere, such as by flushing with nitrogen gas, as is customary in the art.

Measurement of Mucosal Permeation Rates The permeation rates and corresponding mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 1a-1f were determined according to OECD guidelines (adopted 13 April 2004) using porcine mucosa (esophageal mucosa). determined by in vitro experiments according to. For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. A die-cut area of 0.798 cm ² was punched out of the transmucosal treatment system and applied to the mucosa, and the top surface of the mucosa with the transmucosal treatment system was submerged in artificial saliva (the bottom surface was in contact with the receiving medium and the top surface was 1 cm2). compartmentalized into a mucosal area of .145 cm ² ). The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Table 1.2 and Figure Ia.

Agomelatine Utilization Agomelatine utilization at 7 hours was calculated based on cumulative permeation and initial agomelatine content at 7 hours. The results are shown in Table 1.3 and Figure 1b.

In vitro experiments show good mucosal permeation rate and good utilization. In particular, Example 1a without a backing layer shows a fast release of the active substance. However, Examples 1b-1d show that good transmission is obtained even when a backing layer is used. Also, increasing the areal weight (and hence the amount of active agent) increases the permeation rate. Similarly, increasing the amount of active by varying the concentration of active also leads to increased permeation rates (Examples 1e and 1f).

Example 2
Preparation of Permeation Samples In Example 2, the mucosal permeation rate of pure agomelatine in natural saliva was determined for the transmucosal therapeutic systems of Examples 1a and 3a. Therefore, in Example 2, instead of a transmucosal therapeutic system, an agomelatine-containing solution was prepared from 0.877 mg agomelatine in 300 μl of natural saliva.

Mucosal Permeation Rate Measurements Permeation rates and corresponding transmucosal therapeutic systems prepared according to Examples 1a (with some crystalline material), 3a (without crystals) and agomelatine solution above (Example 2) Mucosal permeation rates were determined by in vitro experiments according to OECD guidelines (adopted on 13 April 2004) using porcine mucosa (esophageal mucosa). For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. For Examples 1a and 3a, die-cuts of 0.798 cm ² area were punched out of the transmucosal treatment system and applied to the mucosa. The upper surface of the mucosa with the transmucosal treatment system was immersed in 300 μl of natural saliva (the lower surface is in contact with the receiving medium and the upper surface is compartmentalized into a mucosal area of 1.595 cm ² ). For Example 2, instead of applying the transmucosal treatment system and adding natural saliva, the above permeate sample was applied directly to the mucosa (also having an area of 1.595 cm ² ) and the API content per mucosa area The amount was about 0.55 mg/cm ² . The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Table 2.1 and Figure 2a.

Agomelatine Utilization Agomelatine utilization at 7 hours was calculated based on cumulative permeation and initial agomelatine content at 7 hours. The results are shown in Table 2.2 and Figure 2b.

In vitro experiments show good mucosal permeation rates and good availability.

Examples 3A-3H
Coating Compositions The formulations of agomelatine-containing coating compositions of Examples 3a-3h are summarized in Tables 3.1 and 3.2 below. Formulations are based on weight percentages, as also shown in Tables 3.1 and 3.2.

Preparation of First Coating Composition (Agomelatine-Containing Layer) For Example 3a, a beaker was filled with agomelatine. Ethanol, Eucalyptol, Menthol, Methyl Salicylate, Novamint Fresh Peppermint, Colifer RH 40, FD&C Red No. 40, Sucralose, and Polysorbate 80 were added and the mixture was then stirred. Polyvinylpyrrolidone was added under stirring to give a clear, red solution after stirring for about 2.5 hours.

For Examples 3b-3h, the same coating composition was used for the agomelatine-containing layer, which was prepared as follows: A beaker was filled with agomelatine. Ethanol, Menthol, Eucalyptol, Methyl Salicylate, Colifer RH 40, FD&C Red No. 40, Sucralose, and Polysorbate 80 were added and the mixture was then stirred. A clear solution was obtained. After adding polyvinylpyrrolidone and stirring overnight, Novamint fresh peppermint was added dropwise under stirring to give a clear, red solution.

Preparation of Second Coating Composition (Backing Layer) For Example 3c, a beaker was filled with ethyl cellulose. Ethanol was added and then the mixture was stirred. Castor oil was added under stirring to give a slightly opaque mixture.

For Examples 3e-3h, the beaker was filled with ethanol. Purified water and Kollidon were added and then the mixture was stirred to obtain a solution. Eudragit and glycerol were added under stirring to obtain a clear mixture. For Examples 3f and 3g, sodium hydroxide solution was added to bring the pH as shown in Table 3.2 above.

The resulting second coating compositions of Examples 3c and 3e-3h were coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner), respectively, Dry for approximately 10 minutes at room temperature and 20 minutes at 70° C. (Example 3c), and approximately 5 minutes at room temperature, 10 minutes at 35° C., and 2 minutes at 80° C. (Examples 3e-3h). rice field. The coating thicknesses were respectively 12.3 g/m ² (Example 3c), 26.8 g/m ² (Example 3e), 26.0 g/m ² (Example 3f), 20.5 g/m ² ( Resulting in areal weights of Example 3g) and 22.9 g/m ² (Example 3h). For Example 3d, a 15 μm thick commercial polyethylene terephthalate film was used as the backing layer.

Coating of the First Coating Composition The resulting agomelatine-containing first coating compositions of Examples 3a and 3b were coated on a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which served as a release liner. ) for approximately 15 minutes at room temperature and 5 minutes at 70° C. (Example 3a), or approximately 5 minutes at room temperature, 10 minutes at 50° C., and 2 minutes at 90° C. (Example 3a), respectively. Example 3b) dried. For Examples 3a and 3b, the dry film is the final agomelatine-containing mucoadhesive layer structure.

The resulting agomelatine-containing first coating compositions of Examples 3c and 3e-3h were coated onto the dried backing layer and coated at room temperature for approximately 5 minutes, at 50° C. for 10 minutes, and at 90° C. for 2 minutes. C. (Examples 3c and 3e-3h).

The coating thicknesses resulted in areal weights of 55.4 g/m ² (Example 3a) and 50.0 g/m ² (3b, 3c and 3e-3h), respectively. The coating process of 3d was the same as that of Examples 3b, 3c and 3e-3h, except that the coating composition was coated onto a 15 μm thick polyethylene terephthalate film, hence the backing layer (polyethylene terephthalate film ) was obtained.

Preparation of Transmucosal Therapeutic Systems The transmucosal therapeutic systems of Examples 3b, 3c and 3e-3h were prepared by laminating a backing layer to the agomelatine-containing layer. The release liner was removed prior to lamination.

Further steps (eg punching out individual devices) were performed as in Example 1.

Measurement of Mucosal Permeation Rates The permeation rates and corresponding mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 3a-3h were determined according to OECD guidelines (adopted 13 April 2004) using porcine mucosa (esophageal mucosa). determined by in vitro experiments according to. For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. A die cut of 0.522 cm ² area was punched out of the transmucosal treatment system and applied to the mucosa, and the top surface of the mucosa with the transmucosal treatment system was immersed in artificial saliva (the bottom surface was in contact with the receiving medium and the top surface was 1 cm2). compartmentalized into a mucosal area of .145 cm ² ). The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 3.3 and 3.4 and Figures 3a and 3b.

Agomelatine Utilization Agomelatine utilization at 6 hours was calculated based on cumulative penetration and initial agomelatine content at 6 hours. The results are shown in Table 3.5 and Figure 3c.

In vitro experiments show good mucosal permeation rate and good utilization. Examples 3c-3h compared to Examples 3a and 3b show that low but still good transmission can be achieved even when a backing layer is used.

Examples 4A-4F
Coating Compositions The formulations of the agomelatine-containing coating compositions of Examples 4a-4f are summarized in Tables 4.1 and 4.2 below. Formulations are based on weight percentages, as also shown in Tables 4.1 and 4.2.

Preparation of First Coating Composition (Agomelatine-Containing Layer) For Example 4a, a beaker was filled with agomelatine. Ethanol, Menthol, Eucalyptol, Methyl Salicylate, Colifer RH 49, FD&C Red No. 40, Sucralose, and Polysorbate 80 were added and the mixture was then stirred. Polyvinylpyrrolidone and Novamint fresh peppermint were added under stirring to obtain a viscose mixture.

For Example 4b, a beaker was filled with ethanol. Eucalyptol, Menthol, Methyl Salicylate, Colifer RH 49, FD&C Red No. 40, Sucralose, and Polysorbate 80 were added and the mixture was then stirred. Hydroxypropyl cellulose, Novamint fresh peppermint, and agomelatine were added under stirring to obtain a viscose mixture.

For Example 4c, a beaker was filled with ethanol. Eucalyptol, Menthol, Methyl Salicylate, Novamint Fresh Peppermint, Colifer RH 49, FD&C Red No. 40, Sucralose, and Polysorbate 80 were added and the mixture was then stirred. Soluplus, Miglyol 812, and agomelatine were added under stirring to obtain a low viscosity mixture.

For Examples 4d, 4e, and 4f, beakers were filled with agomelatine. Ethanol, Eucalyptol, Menthol, Methyl Salicylate, Novamint Fresh Peppermint, Colifer RH 49, FD&C Red No. 40, Sucralose, and Polysorbate 80 were added and the mixture was then stirred. Polyvinylpyrrolidone was added under stirring to obtain a viscose mixture.

Preparation of Second Coating Composition (Backing Layer) For Examples 4e and 4f, a beaker was filled with ethanol. Purified water and FD&C Blue No. 1 were added, then the mixture was stirred. Kollidon, Eudragit and glycerol were added under stirring to obtain a mixture.

The resulting second coating compositions of Examples 4e and 4f were coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and allowed to run for approximately 5 minutes. Dried at room temperature for 10 minutes at 35°C and 2 minutes at 80°C. The coating thickness yielded an areal weight of 47.4 g/ ^m2 .

Adhesive Composition Preparation For Example 4e, a beaker was filled with ethanol. Purified water and menthol were added and the mixture was then stirred. Hydroxyethylcellulose, castor oil, and polysorbate 80 were added under stirring to give an opaque mixture.

For Example 4f, a beaker was filled with ethanol. Menthol was added and the mixture was then stirred. Hydroxypropylcellulose and castor oil were added under stirring to obtain a viscose mixture.

The resulting adhesive compositions of Examples 4e and 4f were coated onto the top backing layer and dried for approximately 5 minutes at room temperature, 10 minutes at 50°C, and 2 minutes at 90°C. . The coating thicknesses resulted in areal weights of 25.2 g/m ² (Example 4e) and 23.5 g/m ² (Example 4f), respectively. Die cuts of size 1.1 cm ² were punched out of the adhesive backing layer.

Coating of the First Coating Composition The resulting agomelatine-containing coating compositions of Examples 4a-4f were applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner). 5 minutes at room temperature, 10 minutes at 50° C., and 2 minutes at 90° C. (Examples 4a-4c) and approximately 5 minutes at room temperature, 15 minutes at 50° C., and 2 minutes, respectively. Dried at 90° C. for minutes (Examples 4d-4f). The coating thicknesses were 49.5 g/m ² (Example 4a), 48.6 g/m ² (Example 4b), 58.5 g/m ² (Example 4c) and 115.4 g/m ² respectively. (Example 4d, Example 4e, and Example 4f) resulted in areal weights.

For Examples 4a-4d, the dry film is the final agomelatine-containing mucoadhesive layer structure. For Examples 4e and 4f, die cuts of size 0.28 cm ² were punched from the dry film and the adherent backing layer was die cut and laminated as described above such that the backing layer evenly extended on all sides of the agomelatine containing layer. to obtain an agomelatine-containing mucoadhesive layer structure.

Preparation of Transmucosal Therapeutic System See Example 1.

Measurement of Mucosal Permeation Rates The permeation rates and corresponding mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 4a-4e were determined using porcine mucosa (esophageal mucosa) according to OECD guidelines (adopted 13 April 2004). determined by in vitro experiments according to. For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. 0.522 cm ² area die-cuts from the transmucosal therapeutic systems of Examples 4a-4d and the above agomelatine-containing mucoadhesive layer structures of Examples 4e and 4f are applied to the mucosa for transmucosal treatment. The upper surface of the mucosa with the system was immersed in artificial saliva (the lower surface is in contact with the receiving medium and the upper surface is compartmentalized into a 1.145 cm ² mucosal area). The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Table 4.3 and Figure 4a.

Agomelatine Utilization Agomelatine utilization at 6 hours was calculated based on cumulative penetration and initial agomelatine content at 6 hours. The results are shown in Table 4.4 and Figure 4b.

In vitro experiments show good mucosal permeation rates and good availability. Examples 4e and 4f compared to Example 4d show that low but still good transmission can be achieved even when a backing layer is used. We also show that hydroxypropylcellulose has similar performance to polyvinylpyrrolidone (see Examples 4a and 4b).

Examples 5A-5D
Coating Compositions The formulations of the agomelatine-containing coating compositions of Examples 4b and 5a-5d are summarized in Table 4.1 above and Table 5.1 below. Formulations are based on weight percent, as also shown in Tables 4.1 and 5.1.

Preparation of First Coating Composition (Agomelatine-Containing Layer) For Examples 5a and 5b, a beaker was filled with agomelatine. Vanilla flavor, ethanol, sucralose, Na saccharine, oleic acid, FD&C Yellow No. 5, hydroxypropylcellulose were added and the mixture was then stirred to obtain a clear mixture.

For Example 5c, a beaker was filled with agomelatine. Polyvinyl alcohol was added and the mixture was stirred to give a white mixture.

Preparation of Second Coating Composition (Backing Layer) For Examples 5b and 5c, a beaker was filled with purified water or ethanol, respectively. FD&C Red No. 40 and hydroxypropylcellulose were added under stirring to give an opaque mixture.

For Example 5d, a beaker was filled with ethanol. Purified water and FD&C Blue No. 1 were added, then the mixture was stirred. Kollidon, Eudragit and glycerol were added under stirring to obtain a mixture.

The resulting second coating compositions of Examples 5b, 5c and 5d were coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner), respectively, Approximately 15 minutes at 40° C. and 15 minutes at 70° C. (Example 5b) and approximately 10 minutes at room temperature, 15 minutes at 40° C., and 10 minutes at 70° C. (Example 5c) and approximately 5 minutes Dry at room temperature for 10 minutes at 35° C. and 2 minutes at 80° C. (Example 5d). The coating thicknesses resulted in areal weights of 105.1 g/m ² (Example 5b), 99.6 g/m ² (Example 5c) and 78.3 g/m ² (Example 5d) respectively. For Example 5c, die cuts of size 0.8 cm ² were punched out of the dry backing layer.

Preparation of Adhesive Composition For Example 5d, a beaker was filled with ethanol. Purified water and methanol were added and then the mixture was stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added under stirring to obtain a homogeneous mixture.

The resulting adhesive composition of Example 5d was coated onto the top backing layer and dried for approximately 5 minutes at room temperature, 10 minutes at 50°C, and 2 minutes at 90°C. The coating thickness resulted in an areal weight of 95.6 g/m ² (Example 5d).

Die cuts of size 0.8 cm ² were punched out of the adhesive backing layer.

Coating of the First Coating Composition The resulting agomelatine-containing coating compositions of Examples 5a, 5c and 5d were coated on a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner. ) for approximately 10 minutes at room temperature, 15 minutes at 40° C., and 10 minutes at 70° C. (Example 5a) and 5 minutes at 70° C. (Example 5c), and approximately 5 minutes, respectively. Dry at room temperature for 15 minutes at 50° C. and 2 minutes at 90° C. (Example 5d). For Example 5a, the dry film is the final agomelatine-containing mucoadhesive layer structure. For Examples 5c and 5d, die-cuts of size 0.28 cm ² were punched from the dry film and the above-described adhesive backing layer was applied to the backing layer or adherent backing layer such that the backing layer evenly extended on all sides of the agomelatine-containing layer. was die-cut and laminated to obtain an agomelatine-containing mucoadhesive layered structure.

The resulting agomelatine-containing first coating composition of Example 5b was coated onto the dried backing layer and dried for approximately 10 minutes at room temperature, 15 minutes at 40°C, and 10 minutes at 70°C. let me

The coating thicknesses were 95.7 g/m ² (Example 5a), 95.9 g/m ² (Example 5b), 82.9 g/m ² (Example 5c) and 115.4 g/m ² respectively. (Example 5d) yielded the areal weight.

Preparation of Transmucosal Therapeutic System See Example 1.

Measurement of Mucosal Permeation Rates The permeation rates and corresponding mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 4b and 5a-5d were measured using porcine mucosa (esophageal mucosa) according to OECD guidelines (adopted 13 April 2004). ) by in vitro experiments. For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. 0.28 cm ² (Example 4b) and 0.8 cm ² (Examples 5a and 5b) area die-cuts from transmucosal therapeutic systems and the above agomelatine-containing mucoadhesive layers of Examples 5c and 5d. The construct was applied to the mucosa and the top surface of the mucosa with the transmucosal treatment system was immersed in artificial saliva (the bottom surface is in contact with the receiving medium and the top surface is compartmentalized to a 1.145 cm ² mucosal area). . The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Table 5.2 and Figure 5a.

Agomelatine Utilization Agomelatine utilization at 6 hours was calculated based on cumulative permeation and initial agomelatine content at 8 hours. The results are shown in Table 5.3 and Figure 5b.

In vitro experiments show good mucosal permeation rates and good availability. Although all formulations show good permeation behavior, Example 4b (release area 0.28 cm ² , mucosal area 1.145 cm ² ) was compared to Examples 5a and 5b (release area 0.8 cm ² , mucosal area cm ² ) demonstrates the important role of the total mucosal area available for permeation in open systems. Thus, Example 5b, which has an agomelatine-containing layer similar to Example 5a but with a backing layer, exhibits permeation as good as that of Example 5a.

Examples 6A-6D
Coating Compositions The formulations of the agomelatine-containing coating compositions of Examples 6a-6d are summarized in Table 6.1 below. Formulations are based on weight percentages, as also shown in Table 6.1.

Preparation of Coating Compositions For Examples 6a-6c, a beaker was filled with agomelatine. Vanilla flavor, ethanol, sucralose, Na saccharine, and oleic acid (Examples 6b and 6c) were added and the mixture was then stirred. Hydroxypropylcellulose was added under stirring to obtain a clear solution.

For Example 6d, a beaker was filled with agomelatine. Vanilla flavor, ethanol, sucralose, Na saccharine, and oleic acid were added and the mixture was then stirred. Titanium dioxide and hydroxypropylcellulose were added under stirring to give a white mixture.

Coating of Coating Compositions The resulting agomelatine-containing coating compositions of Examples 6a-6d were coated onto a polyester film (one side siliconized, 75 μm thick, which may serve as a release liner) and allowed to stand for approximately 10 minutes. Dried at room temperature for 15 minutes at 40°C and 10 minutes at 70°C. The coating thicknesses were 93.8 g/m ² (Example 6a), 93.6 g/m ² (Example 6b), 94.3 g/m ² (Example 6c), and 98.3 g/m ² respectively. (Example 6d) yielded the areal weight. The dry film is not further laminated with an additional backing layer and is therefore the final agomelatine-containing mucoadhesive layer structure.

Preparation of Transmucosal Therapeutic System See Example 1.

Determination of Mucosal Permeation Rates The permeation rates and corresponding mucosal permeation rates of transmucosal therapeutic systems prepared according to Examples 6a-6d were determined using porcine mucosa (esophageal mucosa) according to OECD guidelines (adopted 13 April 2004). determined by in vitro experiments according to. For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. A die cut of 0.524 cm ² area was punched out of the transmucosal treatment system, applied to the mucosa, and the top surface of the mucosa with the transmucosal treatment system was immersed in artificial saliva (the bottom surface was in contact with the receiving medium and the top surface was 1 cm2). compartmentalized into a mucosal area of .145 cm ² ). The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Table 6.2 and Figure 6a.

Agomelatine Utilization Agomelatine utilization at 6 hours was calculated based on cumulative penetration and initial agomelatine content at 6 hours. The results are shown in Table 6.3 and Figure 6b.

In vitro experiments show good mucosal permeation rates and good availability. These examples show that satisfactory permeation behavior can be obtained even at low agomelatine concentrations and that the performance of hydroxypropylcellulose is comparable to that of polyvinylpyrrolidone. We also show that certain amounts of fatty acids also appear to increase the permeation rate (see Example 6b compared to Examples 6a and 6c).

Examples 7A-7G
Coating Compositions The formulations of the agomelatine-containing coating compositions of Examples 4b and 6b-6d are summarized in Tables 4.1 and 6.1 above. The formulations of the agomelatine-containing coating compositions of Examples 7a-7g are summarized in Tables 7.1 and 7.2 below. As also shown in these tables, formulations are based on weight percent.

Preparation of First Coating Composition (Agomelatine-Containing Layer) The first coating composition of Example 7g was prepared similarly to that of Example 4b.

For Examples 7a-7c, a beaker was filled with agomelatine. Ethanol was added and then the mixture was stirred. Povidone K90 and Povidone K30 (Example 7a), Hydroxypropyl cellulose (Example 7b) and Povidone K90 (Example 7c) respectively were added under stirring to obtain a viscose mixture.

For Example 7d, a beaker was filled with agomelatine. Polyvinyl alcohol was added and the mixture was stirred to give a white mixture.

For Example 7e, a beaker was filled with polyvinyl alcohol. Purified water was added, then the mixture was stirred and heated to 95°C. Vanilla flavor, sucralose, sodium saccharine, oleic acid and agomelatine were added under stirring to obtain a viscose mixture.

For Example 7f, a beaker was filled with agomelatine. Ethanol, vanilla flavor, sucralose, Na saccharin, oleic acid, and FD&C Yellow No. 5 were added and the mixture was then stirred. Hydroxypropyl cellulose was added under stirring to obtain a viscose mixture.

Coating the First Coating Composition Coating the resulting agomelatine-containing coating composition of Examples 7a-7f onto a polyester film (siliconized on one side, 75 μm thick, which can serve as a release liner), Approximately 10 minutes at room temperature, 15 minutes at 40° C., and 10 minutes at 70° C. (Examples 7a-7c and 7f) and 5 minutes at 70° C. (Example 7d) and 15 minutes at 70° C. ( Example 7e) Dried. The coating thicknesses were 104.4 g/m ² (Example 7a), 103.2 g/m ² (Example 7b), 100.7 g/m ² (Example 7c), 82.9 g/m ² (Example 7d), 98.4 g/m ² (Example 7e), and 95.7 g/m ² (Example 7f).

The resulting agomelatine-containing coating composition of Example 7g was coated onto a polyester film (one side siliconized, 75 μm thick, which may serve as a release liner) and coated at room temperature for approximately 5 minutes and 50 minutes for 15 minutes. °C and 90°C for 2 minutes. The coating thickness yielded an areal weight of 115.4 g/m ² .

Die cuts of size 0.28 cm ² were punched out of the dried agomelatine-containing layer.

Preparation of Second Coating Composition (Backing Layer) For Examples 7a-7d and 7g (same backing layer), and for Examples 7e and 7f (same backing layer), a beaker was filled with vanilla flavor. Sucralose, saccharin, oleic acid, ethanol, purified water, FD&C red, and polyethylene glycol (Examples 7a-7d and 7g) and glycerol (Examples 7e and 7f) respectively were added and the mixture was then stirred. Kollidon and Eudragit were added under stirring to obtain a clear solution.

The resulting second coating composition was coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) and dried for approximately 10 minutes at room temperature for 15 minutes. Dried at 40°C and 70°C for 5 minutes. The coating thickness resulted in areal weights of 92.2 g/m ² (7a-7d and 7g) and 81.2 g/m ² (Examples 7e and 7f), respectively.

Die cuts of size 0.8 cm ² were punched out of the dried backing layer.

Preparation of Transmucosal Therapeutic Systems For Examples 7a-7d and 7g, die-cut the agomelatine-containing layer and add a small amount of 23.5% ethanolic PVP90 so that the backing layer extends evenly on all sides of the agomelatine-containing layer. A solution was used to adhere to the die cut of each backing layer and then laminated to yield an agomelatine-containing mucoadhesive layer structure. For Examples 7e and 7f, the dry film was laminated with its respective backing layer, also such that the backing layer evenly extended on all sides of the agomelatine-containing layer, to provide an agomelatine-containing mucoadhesive layer structure.

Further steps (eg punching out individual devices) were performed as in Example 1.

Mucosal Permeation Rate Measurements The permeation rates and corresponding mucosal permeation rates of the transmucosal therapeutic systems prepared according to Examples 4b, 6b-6d, and 7a-7g were measured according to OECD guidelines (2004) using porcine mucosa (esophageal mucosa). (adopted April 13, 2009)). For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. The agomelatine-containing mucoadhesive layer structure described above was applied to the mucosa and the top surface of the mucosa with the transmucosal therapeutic system was immersed in artificial saliva (the bottom surface was in contact with the receiving medium and the top surface was in contact with the receptive medium and the top surface had a mucosal area of 1.145 cm ² ). are compartmentalized). The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 7.3 and 7.4 and Figures 7a and 7b.

Agomelatine Utilization Agomelatine utilization at 4 hours was calculated based on cumulative permeation and initial agomelatine content at 4 hours. The results are shown in Table 7.5 and Figure 7c.

In vitro experiments show good mucosal permeation rates and good availability. These examples show that satisfactory permeation behavior can be obtained even at low concentrations of agomelatine and that the performance of hydroxypropylcellulose and polyvinyl alcohol is comparable to that of polyvinylpyrrolidone (Examples 7b, 7c and 7d).

Examples 8A-8C
Coating Compositions The formulations of agomelatine-containing coating compositions of Examples 4b, 8a, and 8b are summarized in Table 4.1 above and 8.1 below. Formulations are based on weight percent, as also shown in Tables 4.1 and 8.1.

Preparation of First Coating Composition (Agomelatine-Containing Layer) For Examples 8a-8c, a beaker was filled with agomelatine. Ethanol, Eucalyptol, Menthol, Methyl Salicylate, Novamint Fresh Peppermint, Colifer RH 40, Sucralose, FD&C Red No. 40, and Polysorbate 80 were added and the mixture was then stirred. Povidone was added under stirring to obtain a viscose mixture.

Coating of the First Coating Composition The resulting agomelatine-containing coating compositions of Examples 8a-8c were coated on a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner). and dried for approximately 10 minutes at room temperature, 15 minutes at 50°C, and 2 minutes at 90°C. The coating thickness yielded an areal weight of 109.7 g/m ² .

For Example 8a, the dry film is the final agomelatine-containing mucoadhesive layer structure. For Examples 8b and 8c, die cuts of size 1.6 cm ² were punched from the dried agomelatine-containing layer.

Preparation of Second Coating Composition (Backing Layer) For Example 8b, a beaker was filled with ethanol. FD&C Green No. 3 was added and the mixture was then stirred. Ethyl cellulose N50F, castor oil and glycerol were added under stirring to obtain a mixture.

A second coating composition of Example 8c was prepared similarly to Example 5d above.

The resulting second coating composition was coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) for approximately 10 minutes at room temperature and 20 minutes. Dried at 70°C (Example 8b) and approximately 5 minutes at room temperature, 10 minutes at 35°C and 2 minutes at 80°C. The coating thicknesses resulted in areal weights of 19.2 g/m ² (Example 8b) and 78.3 g/m ² (Example 8c), respectively.

Preparation of adhesive composition A beaker was filled with ethanol. Purified water and menthol were added and the mixture was then stirred. Hydroxyethyl cellulose, castor oil, and polysorbate 80 were added under stirring to obtain a homogeneous mixture.

The resulting adhesive composition was coated onto the dried backing layer and dried for approximately 5 minutes at room temperature, 10 minutes at 50°C, and 2 minutes at 90°C. The coating thicknesses resulted in areal weights of 42.9 g/m ² (Example 8b) and 95.7 g/m ² (Example 8c), respectively. Die cuts of size 5.5 cm ² were punched out of the dry adherent backing layer.

Preparation of Transmucosal Therapeutic Systems For Examples 8b and 8c, dry films were laminated with respective adhesive backing layers to yield agomelatine-containing mucoadhesive layer structures.

Further steps (eg punching out individual devices) were performed as in Example 1.

In Vivo Studies Using Göttingen Minipigs In vivo experiments using Göttingen minipigs (females, approximately 6-7 months old, weighing 13.8-14.3 kg at the start of the study) were performed to evaluate the delivery of agomelatine. bottom. Four minipigs were used. The transmucosal therapeutic systems of Examples 8a, 8b and 8c, prepared as described above, were administered to the buccal mucosa of one animal each for Examples 8a and 8b and two animals for Example 8c ( 1 system/animal). The total wearing time of the transmucosal treatment system was 4 hours (after 4 hours the application area was washed to remove potential residue of the transmucosal treatment system). No residue was observed in Example 8a and slight residue was observed in Examples 8b and 8c with backing.

Minipigs were maintained under sedation throughout the study.

Blood samples were taken at eight time points after application of the transmucosal therapeutic system. Samples were taken at 0 (pre-treatment), 0.5, 1, 1.5, 2, 4 (immediately before test item removal), 5 and 8 hours. Analysis of plasma samples was performed according to the principles of the OECD Good Laboratory Practices (revised 1997). These principles comply with other international GLP regulations.

Agomelatine concentrations in minipig plasma were determined using validated liquid-liquid extraction followed by LC-MS/MS. All samples taken prior to initiation of treatment were determined to be below the limit of quantitation (0.100 ng/mL).

The measured agomelatine plasma concentrations are summarized in Table 8.2 and shown in Figure 8a.

In addition, immediately after removal of OTF, 4 hours after application and washing of the OTF application side, the condition of the mucous membrane was measured visually and OECD Guideline No. 404 on the Testing of Chemicals adopted on July 28, 2015. : A Draize score was obtained based on the following scoring scheme according to "Acute Skin Irritation/Corrosion".

Four hours after removing the transmucosal therapeutic system, none of the formulations showed irritation (see Table 8.2).

Maximum plasma concentrations were measured 2-4 hours after treatment initiation and ranged from 9.0 to 11.8 ng/mL for OTF according to Examples 8b and 8c with backing and 57 for OTF according to Example 8a without backing. .2 ng/mL. Very high PK data could be achieved for the transmucosal therapeutic system according to Example 8a without backing. This can be explained by an open system that allows APIs to be delivered through the mucous membranes of the entire oral cavity. A high delivery rate is still highly advantageous as patch size and/or active agent concentration can be reduced compared to systems that include a backing layer. A transmucosal therapeutic system with a backing layer is limited in permeation area to 1.6 cm ² but exhibits lower but still high permeability over 4 hours. Since agomelatine was quantifiable 4 hours after removal of the transmucosal treatment system with higher PK data, potential residual agomelatine may be intramucosal.

Examples 9A-9F
Coating Compositions The formulations of agomelatine-containing coating compositions of Examples 4b and 9a-9f are summarized in Table 4.1 above and Table 9.1 below. Formulations are based on weight percentages, as also shown in Tables 4.1 and 9.1.

Preparation of the First Coating Composition (Agomelatine-Containing Layer) For the _TiO2 solution, a beaker was filled with 2.80 g of _TiO2 . Oleic acid was added and then the mixture was stirred to obtain a _TiO2 solution.

For Examples 9b, 9c and 9d, the beaker was filled with vanilla flavor. Sucralose, Saccharin Na, Ethanol, Hydroxypropylcellulose GF, Hydroxypropylcellulose EF, Carbopol solution, and Agomelatine were added and the mixture was then stirred. The _TiO2 solution was added under stirring to obtain a viscose mixture.

For Example 9a, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, agomelatine, and ethanol were added and the mixture was then stirred. TiO ₂ solution and hydroxypropylcellulose were added under stirring to obtain a viscose mixture.

For Examples 9e and 9f, the beaker was filled with vanilla flavor. Sucralose, saccharin Na, and ethanol were added and the mixture was then stirred. Carbopol solution, ethyl cellulose, hydroxypropyl cellulose, agomelatine, and TiO ₂ solution were added under stirring to obtain a viscose mixture.

Coating of the First Coating Composition The resulting agomelatine-containing coating composition is coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which can serve as a release liner) to approximately 10 minutes at room temperature, 15 minutes at 40°C, and 10 minutes at 70°C. The coating thicknesses resulted in areal weights of 117.0 g/m ² (Examples 9a-9d), 123.5 g/m ² (Example 9e), and 117.5 g/m ² (Example 9f), respectively. rice field.

For Examples 9a and 9b, the dry film is the final agomelatine-containing mucoadhesive layer structure. For Example 9d, die cuts of size 0.28 cm ² were punched out of the dried agomelatine-containing layer.

Preparation of Second Coating Composition (Backing Layer) For Examples 9c-9f, a beaker was filled with vanilla flavor. Sucralose, Na saccharin, oleic acid, FD&C Red No. 40, ethanol, and purified water were then stirred into the mixture. Hydroxypropyl cellulose and hydroxyethyl cellulose were added under stirring to obtain a viscose mixture.

The resulting backing composition was applied over the dried agomelatine-containing layer (for Examples 9c, 9e and 9f) or a polyester film (polyethylene terephthalate film, siliconized on one side, 75 μm thick, which served as a release liner). obtained) and dried for approximately 10 minutes at room temperature, 15 minutes at 50°C, and 10 minutes at 80°C. The coating thickness was 382 g/cm ² (Example 9c), 272.2 g/m ² (Example 9d) or 388.1 g/m ² (Examples 9e and 9f) total areal weight (agomelatine-containing layer and backing). layer).

For Examples 9c, 9e and 9f, die-cuts of size 0.28 cm ² were punched from the dried layer to yield agomelatine-containing mucoadhesive layer structures.

For Example 9d, die cuts of size 0.28 cm ² were punched from the backing layer and coated with a small amount of the second coating composition such that the backing layer evenly extended on all sides of the agomelatine-containing layer. Adhered to each agomelatine-containing layer, an agomelatine-containing mucoadhesive layer structure was obtained.

Preparation of Transmucosal Therapeutic System See Example 1.

Measurement of Mucosal Permeation Rates The permeation rates and corresponding mucosal permeation rates of the transmucosal therapeutic systems prepared according to Examples 4b and 9a-9f were measured using porcine mucosa (esophageal mucosa) according to OECD guidelines (13 April 2004). Adopted by Japan) by in vitro experiments. For all transmucosal therapeutic systems, a dermatome was used to prepare a 400 μm thick mucosa with intact barrier function. A 0.28 cm ² area die-cut from the transmucoasl therapeutic system of Examples 9a and 9b, and the agomelatine-containing mucoadhesive layer structure described above, was applied to the mucosa to produce the transmucosal therapeutic system. The upper surface of the accompanying mucosa was immersed in artificial saliva (the lower surface is in contact with the receiving medium and the upper surface is compartmentalized into a 1.145 cm ² mucosal area). The amount of agomelatine permeation in the receiving medium (phosphate buffer pH 7.4) at a temperature of 37±1° C. was measured and the corresponding mucosal permeation rate was calculated. The results are shown in Tables 9.2 and 9.3 and Figure 9a.

Agomelatine Utilization Agomelatine utilization at 4 hours was calculated based on cumulative permeation and initial agomelatine content at 4 hours. The results are shown in Table 9.4, Figure 9c.

In vitro experiments show good mucosal permeation rate and good utilization. These examples again demonstrate that transmucosal therapeutic systems with a backing layer provide lower but still good active agent delivery when compared to those without a backing layer.

Determination of Storage Stability Long-term storage stability tests were performed on Examples 9a-9c under different test conditions, namely storage at 25° C. and 60% relative humidity (RH), and 40° C. and 75% RH. bottom. samples were taken from the transmucosal therapeutic system after 3, 6, 9 and 12 months of storage at 25°C and 60% RH, and after 3 and 6 months of storage at 40°C and 75% RH; Ethanol and water content were determined and the amount of agomelatine, as well as various potential degradants, were determined based on specific quantitation of agomelatine content calculated from the (actual) areal weight of the transmucosal therapeutic system tested. Determination by analytical HPLC method. The results are shown in Tables 9.5-9.8 and Figures 9c and 9d.

Stability data show that initial and storage stability is superior for Examples 9a and 89c, both in terms of the amount of agomelatine (especially with respect to the amount of agomelatine remaining after storage) and total potential degradants. show.

dissolution experiment 10
As outlined in more detail above, the soluble film former is preferably soluble, dispersible, or otherwise disintegratable in an aqueous medium such as water, while soluble in, for example, ethanol. is also preferred.

To observe the dissolution behavior of potential film formers, 10 wt% (+/- 0.1 percentage points) mixtures of the polymer in water, ethanol or a 1:1 water/ethanol mixture were prepared and the dissolution behavior was recorded. Viscosity as well as other observations were recorded. Results are summarized in Table 10.1 below.

Examples 11A-11I
Coating Compositions The formulations of agomelatine-containing coating compositions of Examples 11a-11i are summarized in Tables 11.1 and 11.2 below. Formulations are based on weight percent, as also shown in Tables 11.1 and 11.2.

Preparation of the First Coating Composition (Agomelatine-Containing Layer) For the _TiO2 solution, a beaker was filled with 2.80 g of _TiO2 . Oleic acid was added and then the mixture was stirred to obtain a _TiO2 solution.

For Examples 11a, 11f and 11g, the beaker was filled with vanilla flavor. Sucralose, saccharin Na, and ethanol were added and the mixture was then stirred. Carbopol solution, hydroxypropyl cellulose, agomelatine, and TiO ₂ solution were added under stirring to obtain a viscose mixture.

For Examples 11b and 11i, the beaker was filled with vanilla flavor. Sucralose, Na saccharin, and purified water were added and the mixture was then stirred. Carbopol solution, polyvinyl alcohol, agomelatine and _TiO2 solution were added under stirring to obtain a viscose mixture.

For Examples 11c and 11h, the beaker was filled with vanilla flavor. Sucralose, Saccharin Na, Ethanol, and Carbopol solution were added and the mixture was then stirred. Povidone, agomelatine and _TiO2 solutions were added under stirring to obtain a viscose mixture.

For Example 11d, a beaker was filled with vanilla flavor. Sucralose, Saccharin Na, Ethanol, Hydroxypropylcellulose GF, Hydroxypropylcellulose EF, Carbopol solution, and Agomelatine were added and the mixture was then stirred. The _TiO2 solution was added under stirring to obtain a viscose mixture.

For Example 11e, a beaker was filled with vanilla flavor. Sucralose, saccharin Na, and ethanol were added and the mixture was then stirred. Carbopol solution, ethyl cellulose, hydroxypropyl cellulose, agomelatine, and TiO ₂ solution were added under stirring to obtain a viscose mixture.

Coating of the First Coating Composition The resulting agomelatine-containing coating composition was coated onto a polyester film (polyethylene terephthalate film, siliconized on one side, 75μ thick, capable of functioning as a release liner), each having approximately Dried for 10 minutes at room temperature, 15 minutes at 40° C., and 10 minutes at 70° C. (Examples 11a and 11c-11h) and 10 minutes at 80° C. (Examples 11b and 11i). The coating thicknesses were respectively 119.8 g/m ² (Examples 11a and 11g), 160.5 g/m ² (Example 11b), 126.3 g/m ² (Example 11c), 126.0 g/m ² (Example 11d), 120.6 g/m ² (Example 11e), 116.5 g/m ² (Example 11f), 125.2 g/m ² (Example 11h), and 149.9 g/m ^{2 .} (Example 11i) yielded the areal weight.

Preparation of Second Coating Composition (Backing Layer) For Examples 11a-11c, a beaker was filled with vanilla flavor. Sucralose, Na saccharin, oleic acid, FD&C Red No. 40, ethanol, purified water and hydroxypropyl cellulose were added and the mixture was then stirred. Hydroxyethylcellulose was added under stirring to obtain a mixture.

For Examples 11d-11i, the beaker was filled with vanilla flavor. Sucralose, Na saccharin, oleic acid, glycerol, FD&C Red No. 40, ethanol and purified water were added and the mixture was then stirred. Hydroxypropylcellulose and Eudragit L100-55 were added under stirring to give a red mixture.

The resulting backing composition was coated twice over the dried agomelatine-containing layer and dried at 50° C. for approximately 15 minutes and 80° C. for 10 minutes (Examples 11a-11c), or It was coated once over the agomelatine-containing layer and dried at 40° C. for approximately 15 minutes and 70° C. for 10 minutes (for Examples 11d-11i).

The coating thicknesses were respectively 390.6 g/m ² (Example 11a), 446.6 g/m ² (Example 11b), 404.3 g/m ² (Example 11c), 239.0 g/m ² ( Example 11d), 237.2 g/m ² (Example 11e), 237.0 g/m ² (Example 11f), 237.9 g/m ² (Example 11g), 256.7 g/m ² (Example 11h), and resulted in a total areal weight (agomelatine-containing layer and backing layer) of 259.4 g/m ² (Example 11i).

A die-cut with a size of 0.8 cm ² was punched out of the dried layer to obtain an agomelatine-containing mucoadhesive layer structure.

Preparation of Transmucosal Therapeutic System See Example 1.

Mucoadhesion test 12
As outlined in more detail above, the agomelatine-containing layer not only needs to exhibit suitable dissolution behavior, but it also needs to provide sufficient adhesion to mucous membranes. If present, the backing layer in combination with the agomelatine-containing layer should not delaminate from the agomelatine-containing layer and preferably should not dissolve faster than the agomelatine-containing layer.

To observe the dissolution behavior and mucoadhesion of certain combinations of agomelatine-containing layers and backing layers, mucoadhesion experiments using porcine mucosa (esophageal mucosa) were performed as described in Examples 9c, 9e, 9f and 11a-11i. transmucosal treatment system.

Experimental Setup For all transmucosal therapeutic systems, 400 μm thick mucosa with intact barrier function was prepared using a dermatome, outlined above for Examples 9c, 9e, 9f and 11a-11i. A die-cut of 0.8 cm ² area prepared as described was applied to the mucosa. Two samples were prepared for each example (n=2). The upper surface of the mucosa with the transmucosal treatment system was immersed in 300 μl of artificial saliva (the lower surface is in contact with 250 μm of artificial saliva and the upper surface is compartmentalized into 4 cm ² of mucosal area in 50 μl of artificial saliva). . The dissolution behavior and mudoadhesive properties of the transmucosal therapeutic system were evaluated visually initially (2 minutes after application) and periodically at certain time points after application and by using the tip of a plastic syringe plunger upside down. and decided.

Results All samples showed very good initial mucoadhesion, ie samples could not be displaced.

For Example 9c, the two samples were completely dissolved after 4 and 6 hours, respectively. None of the samples could be displaced during this time.

In the sample of Example 9e, after 2 hours and 15 minutes, pieces of the transmucosal treatment system began to disintegrate at the edges. The stripped portion can be displaced. The first sample was completely dissolved after 4.5 hours. A second sample was almost completely dissolved after 6 hours and the remainder could be displaced.

Both samples of Example 9f left only a small residue after 6 hours, indicating good adhesion to the mucosa and could not be displaced.

The first sample of Example 11a was almost completely dissolved and displaced (off center) when visually inspected after 5 hours, and completely dissolved after 5 hours and 20 minutes. A second sample of Example 11a left a small residue after 6 hours, which indicated good adhesion to the mucosa and could not be displaced.

Both samples of Example 11b rolled up about 1 minute after application and did not adhere further to the mucosa. After 3 minutes, the sample unrolled on itself and reattached. The backing layer was completely dissolved after 1.5 hours, at which point the agomelatine-containing layer was still present. The agomelatine-containing layer began to dissolve after 2.5 hours and completely dissolved after 5 hours for the first sample. In the second sample, some residual fragments of the agomelatine-containing layer were still floating on the mucosa after 5.5 hours.

For Example 11c, the agomelatine-containing layer dissolved after 1.5 hours, at which point the backing layer was still present. After 6 hours a gelatinous residue remained which could be displaced. Both samples behaved similarly.

Both samples of Example 11d could be displaced after about 1 hour.

The Example 11e sample could be displaced after about 3/4 hour and about 1 hour, respectively.

Both samples of Example 11f could be displaced with a little force after about 3/4 hours and easily displaced after about 1 hour.

The first sample of Example 11g could be displaced after about 1/2 hour. A second sample of Example 11g could be displaced after 6 minutes, but adhered firmly after a further 4 minutes. After a total of about 1/2 hour, the second sample could be displaced again.

Both samples of Example 11h could be displaced after about 1/2 hour.

Both samples of Example 11i rolled up immediately upon immersion in artificial saliva and remained coiled. The rolled-up sample could be displaced after about 1/2 hour.

These results are summarized in Table 12.1 below. If two samples gave different results, both results are shown separated by a comma.

Abbreviations used in Table 12.1 are as follows:
HPC: Hydroxypropyl cellulose EC: Ethyl cellulose PVA: Polyvinyl alcohol System: Transmucosal therapeutic system AL: Agomelatine-containing layer BL: Backing layer

Water absorption experiment 13
Certain soluble film formers exhibit hygroscopic behavior. To evaluate water absorption over time, different coating compositions were prepared, films were obtained by coating the coating compositions and drying the coated layers. Films were stored open or packaged in seam-sealed pouches at room temperature for 7 days. The detailed composition of the coated films, the drying conditions and the results obtained are given in Table 13.1 below.

The invention particularly relates to the following further items.

1. A transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layered structure, said mucoadhesive layered structure comprising:
A) a backing layer; and B)
i) agomelatine; and ii) an agomelatine-containing layer comprising a first dissolvable film-forming agent.

2. Water, artificial or natural saliva, or any other aqueous medium when said first soluble film former is cast into a film having an areal weight of 30-100 g/m ² , or 50 g/m ² at 37° C. and 150 rpm for less than 5 hours, less than 3 hours, less than 2 hours, or less than 1 hour, or greater than 5 seconds, greater than 30 seconds, greater than 1 minute, or greater than 2 minutes, or greater than 5 seconds and less than 5 hours , greater than 30 seconds and less than 3 hours, greater than 1 minute and less than 2 hours, or greater than 2 minutes and less than 1 hour.

3. The first soluble film former is a polymer such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers. , polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, and natural film formers such as shellac, pectin. , gelatin, alginate, pullulan and starch derivatives, and any mixture thereof.

4. The first soluble film former is a polymer such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers, polyvinyl alcohol. - polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl methacrylate copolymer, and any mixtures thereof, item 3. A transmucosal therapeutic system as described in .

5. 5. The transmucosal therapeutic system of item 4, wherein the first dissolvable film former is hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose.

6. Item wherein said first soluble film former is hydroxypropyl cellulose or a mixture of one or more polymers selected from hydroxypropyl cellulose and ethyl cellulose having a molecular weight of 50,000 to 1,500,000. 6. The transmucosal therapeutic system according to 5.

7. wherein said first soluble film former is hydroxypropyl cellulose or between 75,000 and 85,000, especially 80,000
Between 90,000 and 100,000, especially 95,000
between 350,000 and 400,000, especially 370,000 and between 1,100,000 and 1,200,000, especially 1,150,000,
7. The transmucosal therapeutic system of item 6, which is a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose having a molecular weight selected from:

8. wherein said first soluble film former is hydroxypropylcellulose having a molecular weight between 90,000 and 100,000, especially 95,000; a mixture of one or more polymers selected from hydroxypropylcellulose having a molecular weight of between 350,000 and 400,000, especially hydroxypropylcellulose having a molecular weight of between 370,000 and ethylcellulose, especially 75,000 to 85 ,000, especially 80,000, and a mixture of hydroxypropylcellulose with a molecular weight of between 350,000 and 400,000, especially 370,000, or between 75,000 and 85,000, especially 8. The transmucosal therapeutic system of item 7, which is a mixture of hydroxypropyl cellulose and ethyl cellulose having a molecular weight of 80,000.

9. The amount of the first soluble film former is at least 65%, at least 70%, or at least 75% by weight of the agomelatine-containing layer, or the amount of the first soluble film former is , 98% by weight or less, 94% by weight or less or 90% by weight or less, or the amount of said first soluble film former is between 65 and 98% by weight, between 70 and 94% by weight % range.

10. When the transmucosal therapeutic system is administered to a human patient, the backing layer may remain for 5 minutes or more, 10 minutes or more, or 15 minutes or more, or 12 hours or less, 8 hours or less, or 4 hours or less, or 5 minutes to 12 minutes. 10. The transmucosal therapeutic system of any one of items 1-9, dissolving between 10 minutes and 8 hours, or between 15 minutes and 4 hours.

11. the backing layer in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for 10 minutes or more, 15 minutes or more, or 30 minutes or more, or 15 hours or less, 12 hours or less; Alternatively, the transmucosal therapeutic system according to any one of items 1 to 10, which dissolves in 10 hours or less, or between 10 minutes and 15 hours, between 15 minutes and 12 hours, or between 30 minutes and 10 hours. .

12. 12. The transmucosal therapeutic system of any one of items 1-11, wherein the backing layer comprises a second dissolvable film former.

13. The second soluble film former is a polymer such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers. , polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, and natural film formers such as shellac, pectin. , gelatin, alginates, pullulan and starch derivatives, and any mixture thereof.

14. 14. The transmucosal therapeutic system of item 13, wherein said second dissolvable film former is a mixture of hydroxyethylcellulose and hydroxypropylcellulose.

15. said second soluble film former comprising hydroxyethyl cellulose and a molecular weight of 50,000 to 1,500,000, especially
Between 75,000 and 85,000, especially 80,000
Between 90,000 and 100,000, especially 95,000
an item which is a mixture of hydroxypropyl celluloses having a molecular weight selected between 350,000 and 400,000, especially 370,000, and between 1,100,000 and 1,200,000, especially 1,150,000 15. The transmucosal therapeutic system according to 14.

16. 16. A transmucosal therapeutic system according to item 15, wherein said second dissolvable film former is a mixture of hydroxyethylcellulose and hydroxypropylcellulose with a molecular weight between 75,000 and 85,000, especially 80,000.

17. the ratio of hydroxyethyl cellulose and hydroxypropyl cellulose having a molecular weight between 75,000 and 85,000, especially 80,000 is 1:2 to 8:1, or 1:1 to 4:1, or 2:1.

18. The amount of the second soluble film former is at least 65%, at least 75%, or at least 85% by weight of the backing layer, or the amount of the second soluble film former is 18. The transmucosal therapeutic system of any one of items 1-17, which ranges from 65-100%, 75-100%, or 80-100% by weight.

19. 19. The transmucosal therapeutic system of any one of items 1-18, wherein the size of the backing layer and the size of the agomelatine-containing layer are coextensive.

20. 19. The transmucosal therapeutic system of any one of items 1-18, wherein the backing layer is larger in size and has an increased surface area than the agomelatine-containing layer.

21. 21. The transmucosal therapeutic system of any one of items 1-20, wherein the agomelatine-containing layer comprises at least 1% by weight agomelatine, at least 2% by weight agomelatine, or at least 3% by weight agomelatine.

22. 22. The transmucosal therapeutic system of any one of items 1-21, wherein the agomelatine-containing layer comprises no more than 25% by weight agomelatine, no more than 20% by weight agomelatine, or no more than 10% by weight agomelatine.

23. 23. The transmucosal membrane according to any one of items 1 to 22, wherein the agomelatine-containing layer comprises 1 to 25% by weight or less of agomelatine, 2 to 20% by weight or less of agomelatine, or 3 to 10% by weight or less of agomelatine. treatment system.

24. The agomelatine-containing layer contains fatty acids, sweeteners, flavorants, colorants, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents and further film formers. 24. The transmucosal therapeutic system of any one of items 1-23, further comprising one or more excipients selected from the group consisting of:

25. 25. The transmucosal therapeutic system of item 24, wherein the agomelatine-containing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

26. said fatty acids are saturated or unsaturated, linear or branched carboxylic acids containing 8 to 24 carbon atoms, especially caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, 26. A transmucosal therapeutic system according to item 25, selected from the group consisting of vaccenic acid, linoleic acid, linoleitic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.

27. 27. The transmucosal therapeutic system of item 26, wherein said fatty acid is oleic acid or linoleic acid.

28. the agomelatine-containing layer comprises one or more fatty acids in an amount of at least 1%, at least 3%, or at least 4% by weight, or an amount no greater than 15%, no greater than 12%, or no greater than 10%; or the transmucosal therapeutic system of any one of items 24-27, comprising an amount of 1-15%, 3-12%, or 4-10% by weight.

29. The group in which the agomelatine-containing layer consists of saccharose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycoside, thaumatin and sodium saccharin 25. The transmucosal therapeutic system of item 24, comprising one or more natural or artificial sweeteners selected from:

30. 30. The transmucosal therapeutic system of item 29, wherein the agomelatine-containing layer comprises one or more natural or artificial sweeteners selected from the group consisting of saccharose, sucralose and sodium saccharin.

31. The agomelatine-containing layer contains at least 0.05% by weight, at least 0.1% by weight or at least 0.3% by weight, respectively, of one or more natural or artificial sweeteners selected from the group consisting of sucralose, saccharose and sodium saccharin. % by weight, or an amount of 2.0% or less, 1.5% or less, or 1.0% or less, or 0.05-2.0%, 0.1-1.5% by weight, Alternatively, the transmucosal therapeutic system according to item 30, containing in an amount of 0.3 to 1.0% by weight.

32. The agomelatine-containing layer contains vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, and ethyl maltol. , 2,4-dithiapentane, ethyl vanillin and eucalyptol, and a flavoring composition, such as peppermint flavor. treatment system.

33. wherein the agomelatine-containing layer contains one or more flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, peppermint flavor and eucalyptol;
in an amount of at least 0.1 wt%, at least 0.3 wt% or at least 0.4 wt%, or an amount of 10 wt% or less, 6 wt% or less, or 4 wt% or less, or 0.1 to 10 wt%, respectively %, in amounts of 0.3-6%, or 0.4-4% by weight, or in total amounts of at least 0.1%, at least 0.5%, or at least 0.7% by weight; or in an amount of 15 wt% or less, 10 wt% or less, or 8 wt% or less, or in an amount of 0.1 to 15 wt%, 0.5 to 10 wt%, or 0.7 to 8 wt%, item 32. The transmucosal therapeutic system according to 32.

34. The agomelatine-containing layer contains titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5′-phosphate, quinoline yellow, orange yellow S, Cochineal, carminic acid, azorubin, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotine, chlorophyll, chlorophyllin, copper complex of chlorophyll and chlorophyllin, green S, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite Ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotene, annatto, bixin, norbixin, paprika extract, capsancyan, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, beet 25. The transmucosal treatment of item 24, comprising one or more colorants selected from the group consisting of root red, betanin, anthocyanins, calcium carbonate, iron oxides and hydroxides, aluminum, silver, gold and lysolrubin BK. system.

35. 25. The transmucosal therapeutic system of item 24, wherein the agomelatine-containing layer comprises one or more additional film-forming agents, wherein the additional film-forming agent is different from the first dissolvable film-forming agent.

36. wherein the agomelatine-containing layer comprises one or more additional film formers;
an amount of at least 2 wt%, at least 5 wt% or at least 10 wt%, or an amount of 40 wt% or less, 30 wt% or less, or 25 wt% or less, or 2-40 wt%, 5-30 wt%, respectively , or in an amount of 10 to 25 wt%, or in total an amount of at least 5 wt%, at least 15 wt%, or at least 20 wt%, or an amount no greater than 40 wt%, no greater than 30 wt%, or no greater than 25 wt% , or in an amount of 5-40%, 15-30%, or 20-25% by weight.

37. The agomelatine-containing layer comprises an ethoxylated sorbitan esterified with a fatty acid, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate, safflower 25. The transmucosal therapeutic system of item 24, comprising one or more solubilizers selected from the group consisting of oleosomes, propanediols and polyethoxylated castor oils.

38. The agomelatine-containing layer comprises one or more solubilizers in an amount of at least 1 wt%, at least 3 wt%, or at least 5 wt%, or no more than 25 wt%, no more than 20 wt%, or 15 wt%, respectively. 38. A transmucosal therapeutic system according to item 37, comprising in an amount of:

39. The agomelatine-containing layer is one or more selected from the group consisting of soy lecithin, sodium phosphate, mono- and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters of mono- and diglycerides, and polyethoxylated hydrogenated castor oil. 25. The transmucosal therapeutic system of item 24, comprising an emulsifier of

40. The agomelatine-containing layer contains one or more emulsifiers in an amount of at least 1 wt%, at least 3 wt%, or at least 5 wt%, respectively, or no more than 25 wt%, no more than 20 wt%, or no more than 15 wt%. 40. The transmucosal therapeutic system of item 39, wherein the transmucosal therapeutic system of claim 39, comprising an amount, or in an amount of 1-25%, 3-20%, or 5-15% by weight.

41. The agomelatine-containing layer is one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides, and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium chain triglycerides. Or the transmucosal therapeutic system of item 24, comprising a plurality of plasticizers.

42. The agomelatine-containing layer contains one or more plasticizers in an amount of at least 0.5 wt%, at least 1 wt%, or at least 5 wt%, or no more than 25 wt%, no more than 20 wt%, or 15 wt%, respectively. % or less, or in an amount of 0.5-25%, 1-20%, or 5-15% by weight.

43. The agomelatine-containing layer contains bile acid, bile salt, bile acid derivative, acylcarnitine, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, terpene, cyclodextrin, cyclodextrin derivative, saponin, saponin derivative, chitosan, EDTA, citric acid. Items 1-42 that do not contain permeation enhancers selected from the group consisting of acids and salicylates in amounts greater than 0.1 wt%, greater than 0.2 wt%, greater than 1 wt%, or greater than 5 wt%. The transmucosal therapeutic system according to any one of .

44. the agomelatine-containing layer comprising diethylene glycol monoethyl ether, dipropylene glycol, levulinic acid, lauryl lactate, lactic acid, dimethylethylene urea, N,N'-dimethylpropylene urea DMPU and N,N-diethyl-meta-toluamide (DEET); selected from the group consisting of 2-(2-ethoxyethoxy)ethanol, 2,5-dimethylisosorbide, propylene glycol monocaprylat, 2-methoxy-4-(prop-2-en-1-yl)phenol and laurocapram 44. The transmucosal therapeutic system of any one of items 1-43, comprising a permeation enhancer.

45. the agomelatine-containing layer contains a permeation enhancer in an amount of at least 1%, at least 2%, or at least 5%, or an amount no greater than 20%, no greater than 15%, or no greater than 10%, respectively; or 45. The transmucosal therapeutic system of any one of items 24-44, comprising an amount of 1-20%, 2-15%, or 5-10% by weight.

46. 46. The transmucosal therapeutic system of any one of items 1-45, wherein the agomelatine-containing layer is substantially free of water.

47. 47. The transmucosal therapeutic system of item 46, wherein the agomelatine-containing layer comprises 12% or less, 8% or less, 5% or less, or 4% or less by weight water.

48. The group wherein said agomelatine-containing layer is substantially free of volatile solvents, said volatile solvents consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixture thereof. in particular selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. mucosal treatment system.

49. 49. The transmucosal therapeutic system of item 48, wherein the agomelatine-containing layer comprises 5 wt% or less, 3 wt% or less, or 1 wt% or less of a volatile solvent.

50. 50. Any one of items 1 to 49, wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprising the agomelatine, the first soluble film former and ethanol. transmucosal therapeutic system.

51. 51. Any one of items 1 to 50, wherein the agomelatine-containing layer is obtainable by drying a coated coating composition comprising the agomelatine, the first soluble film former and water. transmucosal therapeutic system.

52. 52. Transmucosal treatment according to item 50 or 51, wherein said agomelatine-containing layer is obtainable by drying a coated coating composition comprising said agomelatine, said first soluble film former, ethanol and water. system.

53. Item 50, wherein said agomelatine-containing layer is obtainable by drying a coated coating composition comprising less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water. 53. The transmucosal therapeutic system of any one of 1-52.

54. The agomelatine-containing layer has an areal weight of at least 25 g/m ² , at least 35 g/m ² , or at least 40 g/m ² , or no more than 300 g/m 2 , no more than 250 g/ ^{m 2 ,} or no more than 200 g/m ² or have an areal weight of 25-300 g/m ² , 35-250 g/m ² , or 40-200 g/m ^{2 .} system.

55. said agomelatine-containing layer comprises at least 0.1 mg/cm ² , at least 0.2 mg/cm ² , or at least 0.4 mg/cm ² of agomelatine-containing layer, or said agomelatine-containing layer is no more than 2.0 mg/cm ² , 1.5 mg/cm ² or less, or 1.2 mg/cm ² or less of agomelatine, or the agomelatine-containing layer contains 0.1 to 2.0 mg/cm ² , 0.2 to 1.5 mg/cm ² , or 0.4-1.2 mg/cm ² of agomelatine.

56. wherein said agomelatine is present in said agomelatine-containing layer in a dissolved form, a dispersed form, a crystalline form, especially one of its polymorphic forms, an amorphous form, a hydrate, a solvate, a hybrid form of any of the foregoing forms; or mixtures thereof.

57. Said agomelatine-containing layer contains said agomelatine in dissolved form, dispersed form, crystalline form, especially one of its polymorphic forms, amorphous form, hydrates, solvates, hybrid forms of any of the foregoing forms. 57. A transmucosal therapeutic system according to any one of items 1 to 56, obtainable by incorporating as a mixture thereof.

58. 58. The transmucosal therapeutic system of any one of items 1-57, wherein the agomelatine in the agomelatine-containing layer is present in dissolved or dispersed form.

59. 59. The transmucosal therapeutic system of item 58, wherein the agomelatine in the agomelatine-containing layer is present in dispersed form.

60. 59. The transmucosal therapeutic system of item 58, wherein the agomelatine in the agomelatine-containing layer is dissolved.

61. 61. Any of items 1 to 60, wherein at least 90 mol %, preferably at least 95 mol %, more preferably at least 98 mol %, most preferably at least 99 mol % of said agomelatine in said agomelatine-containing layer is present in dissolved form. 10. A transmucosal therapeutic system according to claim 1.

62. 62. The transmucosal therapeutic system of any one of items 1-61, wherein the agomelatine-containing layer does not contain agomelatine crystals.

63. 63. A transmucosal therapeutic system according to any one of items 1 to 62, wherein said agomelatine has a purity of at least 95%, preferably at least 98%, more preferably at least 99% as determined by quantitative HPLC.

64. The backing layer comprises fatty acids, sweeteners, flavorants, colorants, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents and further film formers. 64. The transmucosal therapeutic system of any one of items 1-63, further comprising one or more excipients selected from the group consisting of:

65. 65. The transmucosal therapeutic system of item 64, wherein the backing layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents.

66. said fatty acids are saturated or unsaturated, linear or branched carboxylic acids containing 8 to 24 carbon atoms, especially caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, 66. A transmucosal therapeutic system according to item 65, selected from the group consisting of vaccenic acid, linoleic acid, linoleitic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.

67. wherein said backing layer is from the group consisting of saccharose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin and sodium saccharin 65. The transmucosal therapeutic system of item 64, comprising one or more selected natural or artificial sweeteners.

68. The backing layer contains vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 65. A transmucosal treatment according to item 64, comprising one or more natural or artificial flavors selected from the group consisting of 2,4-dithiapentane, ethylvanillin and eucalyptol, and a flavorant composition, such as peppermint flavor. system.

69. The backing layer comprises titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal. , carminic acid, azorubin, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotine, chlorophyll, chlorophyllin, copper complex of chlorophyll and chlorophyllin, green S, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia Caramel, Brilliant Black BN, Black PN, Vegetable Carbon, Brown HT, Carotene, Annatto, Bixin, Norbixin, Paprika Extract, Capsancyan, Capsorubin, Lycopene, Beta-Apo-8'-Carotenal, Lutein, Canthaxanthin, Beetroot 65. The transmucosal therapeutic system of item 64, comprising one or more colorants selected from the group consisting of red, betanin, anthocyanin, calcium carbonate, iron oxides and hydroxides, aluminum, silver, gold and lysolrubin BK. .

70. 65. The transmucosal therapeutic system of item 64, wherein the backing layer comprises one or more additional film formers, wherein the additional film former is different from the second soluble film former.

71. The backing layer comprises an ethoxylated sorbitan esterified with a fatty acid, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate, safflower oleo 65. The transmucosal therapeutic system of item 64, comprising one or more solubilizers selected from the group consisting of some, propanediol and polyethoxylated castor oil.

72. wherein said backing layer is one or more selected from the group consisting of soy lecithin, sodium phosphate, mono- and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters of mono- and diglycerides, and polyethoxylated hydrogenated castor oil; 65. The transmucosal therapeutic system of item 64, comprising an emulsifier.

73. wherein said backing layer is one selected from the group consisting of monosaccharides, disaccharides, oligosaccharides and polysaccharides, and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium chain triglycerides; 65. The transmucosal therapeutic system of item 64, comprising a plurality of plasticizers.

74. 74. The transmucosal therapeutic system of any one of items 1-73, wherein the transmucosal therapeutic system is substantially free of water.

75. 75. The transmucosal therapeutic system of item 74, wherein the transmucosal therapeutic system comprises 10% or less, 5% or less, or 3% or less by weight water.

76. wherein said backing layer is substantially free of volatile solvents, said volatile solvents from the group consisting of methanol, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixture thereof. 76. Transmucosal according to any one of items 1 to 75, selected from the group consisting of C1-C3 linear and branched alcohols, ethyl acetate, hexane, n-heptane, and any mixtures thereof. treatment system.

77. 77. The transmucosal therapeutic system of item 76, wherein the backing layer comprises 5% or less, 3% or less, or 1% or less by weight of a volatile solvent.

78. 78. The transmucosal therapeutic system of any one of items 1-77, wherein the backing layer is obtainable by drying a coated coating composition comprising the second soluble film former and ethanol. .

79. 79. The transmucosal therapeutic system of any one of items 1-78, wherein said backing layer is obtainable by drying a coated coating composition comprising said second soluble film former and water. .

80. 80. The transmucosal therapeutic system of item 78 or 79, wherein said backing layer is obtainable by drying a coated coating composition comprising said second soluble film former, ethanol and water.

81. wherein said backing layer is obtainable by drying a coated coating composition comprising less than 50% by weight, or less than 20% by weight, or less than 10% by weight, or less than 5% by weight of water, items 78- 80. The transmucosal therapeutic system according to any one of 80.

82. the backing layer has ^an areal weight of at ^least 50 g/m ² , at ^least 75 g/m ² , or at least 100 g/m ² ; 82. The transmucosal therapeutic system of any one of items 1-81, having an areal weight or having an areal weight of 50-400 g/m ² , 75-350 g/m ² , or 100-300 g/m ² . .

83. The mucoadhesive layer structure comprises:
C) a mucosal contact layer, and D) a decorative layer, further comprising one or more additional layers selected from;
When the different layers are present, their order is
83. The transmucosal therapeutic system according to any one of items 1 to 82, which is a decorative layer backing layer agomelatine-containing layer mucosal contact layer.

84. 84. The transmucosal therapeutic system of item 83, wherein said mucoadhesive layer structure further comprises or does not comprise a mucosal contact layer.

85. 85. The transmucosal therapeutic system of item 84, wherein said mucoadhesive layer structure further comprises a mucosal contact layer, said mucosal contact layer being mucoadhesive.

86. 86. The transmucosal of any one of items 83-85, wherein said mucoadhesive layer structure further comprises a mucosal contact layer, wherein the size of said agomelatine-containing layer and the size of said mucosal contact layer are coextensive. treatment system.

87. 87. The transmucosal therapeutic system of any one of items 83-86, wherein said mucoadhesive layer structure further comprises or does not comprise a decorative layer.

88. 88. The transmucosal treatment system of any one of items 83-87, wherein the mucoadhesive layer structure further comprises a decorative layer, wherein the size of the backing layer and the size of the decorative layer are coextensive.

89. Any of items 83-88, wherein the decorative layer dissolves in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm in less than 3 minutes, less than 1 minute, or less than 30 seconds. 10. A transmucosal therapeutic system according to claim 1.

90. 90. The transmucosal therapeutic system of any one of items 1-89, wherein said mucoadhesive layer structure consists of said backing layer and said agomelatine-containing layer.

91. 91. The transmucosal therapeutic system of any one of items 1-90, wherein the agomelatine-containing layer is mucoadhesive.

92. 92. The transmucosal therapeutic system of any one of items 1-91, wherein said mucoadhesive layered structure contains a therapeutically effective amount of agomelatine.

93. The agomelatine-containing layer comprises at least 0.1 mg, at least 0.2 mg, or at least 0.4 mg of agomelatine, or the agomelatine-containing layer comprises no more than 20 mg, no more than 15 mg, or no more than 10 mg of agomelatine, or 93. The transmucosal therapeutic system of any one of items 1-92, wherein the agomelatine-containing layer comprises 0.1 mg to 20 mg, 0.2 mg to 15 mg, or 0.4 mg to 10 mg of agomelatine.

94. said mucoadhesive layer structure in water, artificial or natural saliva, or any other aqueous medium at 37° C. and 150 rpm for 10 minutes or more, 15 minutes or more, or 30 minutes or more, or 15 hours or less; 93. according to any one of items 1-93, dissolving in 12 hours or less, or 10 hours or less, or between 10 minutes and 15 hours, between 15 minutes and 12 hours, or between 30 minutes and 10 hours Transmucosal therapeutic system.

95. The transmucosal therapeutic system has an emission area of at least 0.1 cm ² , at least 0.2 cm ² , or at least 0.5 cm ² , or has an emission area of 10 cm ² or less, 7 cm ² or less, or 5 cm ^{2 or} less. or 0.1-10 cm ² , 0.2-7 cm ² , or 0.5-5 cm ² .

96. 96. The transmucosal treatment system of any one of items 1-95, further comprising a release liner.

97. 96. The transmucosal therapeutic system of any one of items 1-95, wherein the transmucosal therapeutic system does not include a release liner.

98. 98. The transmucosal therapeutic system of any one of items 1-97, wherein the transmucosal therapeutic system is in the form of a film.

99. wherein the transmucosal therapeutic system has an area weight of at least 75 g/m ² , at least 100 g/m ² , or at least 130 g/m ² , or an area of 700 g/m ² or less, 600 g/m ² or less, or 500 g/m ^{2 or} less; 99. The transmucosal therapeutic system of item 98, in the form of a thin film having a weight, or area weight of 75-700 g/m ² , 100-600 g/m ² , or 130-500 g/m ² .

100. 99. The transmucosal therapeutic system of any one of items 1-99, wherein the transmucosal therapeutic system is in the form of a film having a circular, rectangular or square shape.

101. 101. Any of items 1-100, wherein said administration of said transmucosal therapeutic system comprises applying said mucoadhesive layer structure to the mucosa of the oral cavity of a human patient and maintaining it on said mucosa until it dissolves. 10. A transmucosal therapeutic system according to claim 1.

102. Said administration of said transmucosal therapeutic system comprises applying said mucoadhesive layer structure to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient and maintaining it on said mucosa until it dissolves. 102. The transmucosal therapeutic system of item 101, comprising:

103. 103. Any one of items 1-102, wherein the transmucosal therapeutic system provides a mucosal permeation rate of agomelatine between 10 μg/cm ² -hr and 150 μg/cm ² -hr after 1 hour when measured in porcine esophageal mucosa. The transmucosal therapeutic system according to 1.

104. said transmucosal therapeutic system is at least 0.02 mg/cm ² , at least 0.05 mg/cm ² or at least 0.1 mg/cm ² , or 0.5 mg over 8 hours as measured using porcine esophageal mucosa /cm ² or less, 0.4 mg/cm ² or less, or 0.3 mg/cm ² or less, or 0.02 mg/cm ² to 0.5 mg/cm ² , 0.05 mg/cm ² to 0.4 mg/cm ² , or 0.1 mg/cm ² to 0.3 mg/cm ² of agomelatine.

105. 105. A transmucosal therapeutic system according to any one of items 1-104 for use in a method of treating a human patient.

106. 106. A transmucosal therapeutic system according to item 105 for use in a method of treating major depression.

107. for use in a method of treatment, wherein said transmucosal therapeutic system is administered by applying said mucoadhesive layered structure to the oral mucosa of a human patient and remains on said mucosa until dissolved. 107. The transmucosal therapeutic system of item 105 or 106.

108. For use in a method of treatment wherein said transmucosal therapeutic system is administered and dissolved by applying said mucoadhesive layered structure to the oral buccal, sublingual, gingival or palatal mucosa of a human patient. 108. The transmucosal therapeutic system of item 107, maintained on said mucosa up to.

109. 109. The transmucosal therapeutic system of any one of items 105-108, for use in a method of treatment, wherein the transmucosal therapeutic system is administered in the evening or night before bedtime.

110. A method of treatment, wherein the transmucosal therapeutic system of any one of items 1-104 is administered to a human patient.

111. A method of treating major depression according to item 110, wherein the transmucosal therapeutic system according to any one of items 1-104 is administered to a human patient.

112. 106. The transmucosal therapeutic system of any one of items 1-105 is administered by applying said mucoadhesive layered structure to the oral mucosa of a human patient and remains on said mucosa until dissolved. 112. A method of treatment according to item 110 or 111.
113. The transmucosal therapeutic system according to any one of items 1 to 105 is administered by applying said mucoadhesive layered structure to the oral mucosa of a human patient, in particular to the buccal, sublingual, gingival or palatal mucosa. 113. A method of treatment according to item 112, wherein the agent is applied and maintained on the mucosa until dissolution.

114. 114. A method of treatment according to any one of items 110-113, wherein the transmucosal therapeutic system is administered in the evening or at night before bedtime.

115. A process for producing an agomelatine-containing layer, comprising:
i) combining at least agomelatine and a first soluble film former in a solvent to obtain a first coating composition;
ii) coating the first coating composition onto a release liner; and iii) drying the first coated coating composition to form the agomelatine-containing layer.

116. 116. Process according to item 115, wherein in step i) said agomelatine is dissolved.

117. 116. The process of item 115, wherein in step i) said agomelatine is dispersed.

118. 118. The process of any one of items 115-117, wherein said solvent comprises an alcoholic solvent selected from methanol, ethanol, isopropanol and mixtures thereof.

119. 119. The process of item 118, wherein the solvent comprises or consists of ethanol.

120. 120. The process of any one of items 115-119, wherein said solvent comprises water.

121. 120. The process of any one of items 115-119, wherein the solvent does not contain water in an amount of more than 5%, 2%, 1% or 0.5% by weight.

122. 122. The process of any one of items 115-121, wherein drying is carried out at a temperature of 40-90°C, or 60-80°C.

123. step i) combines at least agomelatine, a first soluble film former, and one or more excipients selected from the group consisting of fatty acids, sweeteners, and flavoring agents in a solvent to coat 123. A process according to any one of items 115-122, comprising obtaining a composition.

124. In step i), said agomelatine is in dissolved form, dispersed form, crystalline form, in particular one of its polymorphic forms, amorphous form, hydrates, solvates, hybrid forms of any of the foregoing forms or A process according to any one of items 115-123, combined as a mixture thereof.

125. A process for manufacturing a transmucosal therapeutic system, comprising:
A) manufacturing an agomelatine-containing layer according to items 115-124;
B) a backing layer,
i) dissolving at least a second soluble film former in a solvent to obtain a second coating composition;
ii) coating said second coating composition onto a release liner; and iii) drying said second coated coating composition to form said backing layer; and C) said manufacturing process comprising laminating said resulting agomelatine-containing layer and said backing layer.

126. A process for manufacturing a transmucosal therapeutic system, comprising:
A) manufacturing an agomelatine-containing layer according to items 115-124;
B) a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer,
i) dissolving at least a second soluble film former in a solvent to obtain a second coating composition;
ii) coating said second coating composition onto said agomelatine-containing layer obtained in A); and iii) drying said second coated coating composition and coating onto said agomelatine-containing layer. the manufacturing process comprising preparing by a process comprising the step of forming the backing layer that has been coated.

127. 126. Process according to item 126, wherein step ii) is performed at least once, in particular twice or three times.

128. 128. The process according to any one of items 125 to 127, wherein in B) said solvent comprises one or more of an alcoholic solvent such as methanol, ethanol and isopropanol, and water.

129. 129. The process of any one of items 125-128, wherein said solvent comprises or consists of ethanol.

130. 129. The process of any one of items 125-129, wherein the solvent comprises water.

131. 131. The process of any one of items 125-130, wherein drying is carried out at a temperature of 40-90°C, or 60-80°C.

132. 132. A transmucosal therapeutic system for the transmucosal administration of agomelatine, said transmucosal therapeutic system obtainable by a manufacturing process according to any one of items 126-131.

133. A transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least A) a backing layer; and B)
i) 3-7% by weight agomelatine;
ii) a first soluble film former, and iii) 5-15% by weight fatty acid;
iv) 0.1-2.0% by weight of one or more sweeteners, and v) 0.2-2.0% by weight of a flavoring agent, comprising an agomelatine-containing layer;
wherein said first soluble polymer is hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose;
The area weight of the agomelatine-containing layer is in the range of 100 to 150 g/m ² ,
The backing layer comprises 5-15% by weight fatty acids, 0.1-2.0% by weight one or more sweeteners, 0.2-2.0% by weight flavoring agents, and a second solubility a film former, wherein said second soluble film former is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose;
The transmucosal therapeutic system, wherein the areal weight of the backing layer is in the range of 100-300 g/m ² .

Claims (17)

A transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layered structure, said mucoadhesive layered structure comprising:
A) a backing layer; and B)
i) agomelatine; and ii) an agomelatine-containing layer comprising a first dissolvable film-forming agent. Water, artificial or natural saliva, or any other aqueous medium when said first soluble film former is cast into a film having an areal weight of 30-100 g/m ² , or 50 g/m ² at 37° C. and 150 rpm for less than 5 hours, less than 3 hours, less than 2 hours, or less than 1 hour, or greater than 5 seconds, greater than 30 seconds, greater than 1 minute, or greater than 2 minutes, or greater than 5 seconds and less than 5 hours , greater than 30 seconds and less than 3 hours, greater than 1 minute and less than 2 hours, or greater than 2 minutes and less than 1 hour. The first soluble film former is a polymer such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers. , polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, and natural film formers such as shellac, pectin. , gelatin, alginates, pullulan and starch derivatives, and any mixtures thereof; is a mixture of one or more selected polymers and/or the amount of said first soluble film former is at least 65%, at least 70% or at least 75% by weight of said agomelatine-containing layer or the amount of said first soluble film former is no more than 98 wt%, no more than 94 wt%, or no more than 90% by weight, or the amount of said first soluble film former is 3. The transmucosal therapeutic system of claim 1 or 2, which ranges from 65-98%, 70-94%, or 75-90% by weight. said backing layer comprises a second dissolvable film-forming agent, and/or said backing layer lasts for 5 minutes or more, 10 minutes or more, or 15 minutes or more upon administration of said transmucosal therapeutic system to a human patient; or 12 hours or less, 8 hours or less, or 4 hours or less, or dissolves between 5 minutes and 12 hours, between 10 minutes and 8 hours, or between 15 minutes and 4 hours, any of claims 1 to 3 1. The transmucosal therapeutic system according to claim 1. said backing layer comprising a second soluble film former;
The second soluble film former is a polymer such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol-polyvinyl acetate- and polyvinylcaprolactam-based graft copolymers. , polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, and natural film formers such as shellac, pectin. , gelatin, alginate, pullulan and starch derivatives, and any mixture thereof, and/or said second soluble film former is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose. and/or said second soluble film former is a mixture of hydroxyethylcellulose and hydroxypropylcellulose, the ratio of hydroxyethylcellulose and hydroxypropylcellulose having a molecular weight between 75,000 and 85,000, especially 80,000 is 1:2 to 8:1, or 1:1 to 4:1, or 2:1, and/or the amount of said second soluble film former is greater than said backing at least 65%, at least 75% or at least 85% by weight of the layer, or the amount of said second soluble film former is from 65 to 100%, from 75 to 100%, or from 80% to 5. The transmucosal therapeutic system of Claim 4, in the range of 100% by weight. 6. The method of claim 4 or 5, wherein the size of the backing layer and the size of the agomelatine-containing layer are coextensive, or the backing layer is larger in size and has an expanded surface area than the agomelatine-containing layer. A transmucosal therapeutic system as described. Said agomelatine-containing layer comprises at least 1% by weight agomelatine, at least 2% by weight agomelatine, or at least 3% by weight agomelatine, and/or said agomelatine-containing layer is no more than 25% by weight agomelatine, no more than 20% by weight or 10 wt% or less of agomelatine, and/or the agomelatine-containing layer contains 1 to 25 wt% or less of agomelatine, 2 to 20 wt% or less of agomelatine, or 3 to 10 wt% or less of agomelatine and/or the agomelatine in the agomelatine-containing layer is present in dissolved or dispersed form, and/or the agomelatine-containing layer is free of agomelatine crystals 2. The transmucosal therapeutic system according to item 1. The agomelatine-containing layer and/or the backing layer contains a fatty acid, a sweetener, a flavoring agent, a coloring agent, a permeation enhancer, a solubilizer, a plasticizer, a humectant, a disintegrant, an emulsifier, an antioxidant, a stabilizer, and a buffer. further comprising one or more excipients selected from the group consisting of reagents and additional film forming agents;
In particular, said fatty acids are saturated or unsaturated, linear or branched carboxylic acids containing 4 to 24 carbon atoms, especially caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidin. acid, vaccenic acid, linoleic acid, linoleidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid, and/or in particular, the agomelatine-containing layer contains saccharose, one or more selected from the group consisting of glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin and sodium saccharin and/or in particular the agomelatine-containing layer contains vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, anthranilic acid One or more natural or artificial flavors selected from the group consisting of methyl, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin and eucalyptol, and flavoring compositions A transmucosal therapeutic system according to any one of claims 1 to 7, comprising, for example, peppermint flavor. the agomelatine-containing layer has an areal weight of at least 25 g/m ² , at least 35 g/m ² , or at least 40 g/m ² , or no more than 300 g/m 2 , no ^{more than 250 g/m 2 ,} or no more than 200 g/m ² or has an area weight of 25-300 g/m ² , 35-250 g/m ^{2 , or 40-200 g/m 2 , and/or the backing layer has an area weight of at least 50 g/m 2 , at} least have an area weight of 75 g/m ² , or at least 100 g/m ² , or have an area weight of 400 g/m ² or less, 350 g/m ² or less, or 300 g/m ² or less; ² , has an areal weight of 75-350 g/m ² , or 100-300 g/m ² , and/or the transmucosal treatment system weighs at least 75 g/m ² , at least 100 g/m ² , or at least 130 g/m ² area weight of 700 g/m ² or less, 600 g/m ^{2 or} less, or 500 g/m ² or ^{less ;} 9. The transmucosal therapeutic system of any one of claims 1-8, in the form of a thin film having areal weight. Said mucoadhesive layer structure consists of said backing layer and said agomelatine-containing layer; 10 minutes or more, 15 minutes or more, or 30 minutes or more, or 15 hours or less, 12 hours or less, or 10 hours or less, or between 10 minutes and 15 hours, between 15 minutes and 12 hours, or 30 minutes 10. The transmucosal therapeutic system of any one of claims 1-9, wherein the transmucosal therapeutic system dissolves between-10 hours. said transmucosal therapeutic system provides a mucosal permeation rate of agomelatine between 10 μg/cm ² -hr and 150 μg/cm ² -hr after 1 hour when measured in porcine esophageal mucosa; and/or said transmucosal therapeutic system. is at least 0.02 ^mg /cm 2 , at least 0.05 mg/cm ² or at least 0.1 mg/cm ² , or no more than 0.5 mg/cm ² over 8 hours when measured using porcine esophageal mucosa; 0.4 mg/cm ² or less, or 0.3 mg/cm ² or less, or 0.02 mg/cm ² to 0.5 mg/cm ² , 0.05 mg/cm ² to 0.4 mg/cm ² , or 0.1 mg 11. The transmucosal therapeutic system of any one of claims ^1-10 , which provides a cumulative release of agomelatine of from 0.3 mg/ ^cm2 to 0.3 mg/cm2. A transmucosal therapeutic system according to any one of claims 1-11 for use in a method of treating a human patient. A method of treatment comprising:
The method, wherein the transmucosal therapeutic system of any one of claims 1-11 is administered to a human patient. Said method of treatment is a method of treating major depression and/or said transmucosal therapeutic system irradiates said mucoadhesive layer structure into the mucosa of the oral cavity of a human patient, particularly the buccal, sublingual, gingival or palatal mucosa. 13. The transmucosal treatment of claim 12, administered by application to a mucosa and maintained on said mucosa until dissolved, and/or wherein said transmucosal therapeutic system is administered in the evening or night before bedtime. 14. A system or method of treatment according to claim 13. A process for producing an agomelatine-containing layer, comprising:
i) combining at least agomelatine and a first soluble film former in a solvent to obtain a first coating composition;
ii) coating the first coating composition onto a release liner; and iii) drying the first coated coating composition to form the agomelatine-containing layer. A process for manufacturing a transmucosal therapeutic system, comprising:
A) producing an agomelatine-containing layer according to claim 15,
and B) a backing layer,
i) dissolving at least a second soluble film former in a solvent to obtain a second coating composition;
ii) coating said second coating composition onto a release liner; and iii) drying said second coated coating composition to form said backing layer; and C) laminating the resulting agomelatine-containing layer and the backing layer;
or B) a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer and an agomelatine-containing layer,
i) dissolving at least a second soluble film former in a solvent to obtain a second coating composition;
ii) coating said second coating composition onto said agomelatine-containing layer obtained in A); and iii) drying said second coated coating composition and coating onto said agomelatine-containing layer. the manufacturing process comprising preparing by a process comprising the step of forming the backing layer that has been coated. A transmucosal therapeutic system for transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising at least A) a backing layer; and B)
i) 3-7% by weight agomelatine;
ii) a first soluble film former, and iii) 5-15% by weight fatty acid;
iv) 0.1-2.0% by weight of one or more sweeteners, and v) 0.2-2.0% by weight of a flavoring agent, comprising an agomelatine-containing layer;
wherein said first soluble polymer is hydroxypropylcellulose or a mixture of one or more polymers selected from hydroxypropylcellulose and ethylcellulose;
The area weight of the agomelatine-containing layer is in the range of 100 to 150 g/m ² ,
The backing layer comprises 5-15% by weight fatty acids, 0.1-2.0% by weight one or more sweeteners, 0.2-2.0% by weight flavoring agents, and a second solubility a film former, wherein said second soluble film former is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose;
The transmucosal therapeutic system, wherein the areal weight of the backing layer is in the range of 100-300 g/m ² .

Images